Markers for mature beta-cells and methods of using the same

ABSTRACT

Markers for mature β-cells and methods of using these markers are disclosed.

RELATED APPLICATIONS

This application is a continuation of U.S. patent Ser. No. 14/228,959,filed Mar. 28, 2014, which claims the benefit of U.S. ProvisionalApplication No. 61/806,371, filed Mar. 28, 2013, the entire teachings ofall of which are herein incorporated by reference.

GOVERNMENT SUPPORT

This invention was made with government support under 2 U01 DK072473-07awarded by the National Institutes of Health. The government has certainrights in the invention.

BACKGROUND OF THE INVENTION

The directed differentiation of stem cells has the potential to produceβ-cells for administration to individuals suffering from diseasesassociated with β-cell abnormality (e.g., diabetes). However, existingin vitro differentiation protocols often produce “β-like” cells, whichdo not have the same functional properties as mature β-cells. Inaddition, the complete set of signals and mechanisms governing β-cellmaturation remains unknown.

SUMMARY OF THE INVENTION

The present invention provides solutions to one or more of the problemsoutlined above. In particular, the present invention provides markersfor identifying mature β-cells and methods of using the markers foridentifying mature β-cells, methods of identifying agents that modulatematurity of β-cells (e.g., agents that induce functional β-cellmaturation in vitro, or agents that induce β-cell maturation in vivo),methods of modulating disorders associated with β-cell deficiency, andrelated compositions and methods.

In some aspects, the invention provides a method of detecting β-cells,the method comprising: (a) obtaining a putative β-cell or a populationof putative β-cells to be assessed; (b) measuring expression of aplurality of genes in the putative β-cell or the population of putativeβ-cells to produce a transcriptome of the putative β-cell or thepopulation of putative β-cells; (c) comparing the transcriptome of theputative β-cell or the population of putative β-cells to a referencemature β-cell transcriptome exhibiting a pattern of expression depictedin FIG. 12; and (d) detecting β-cells, wherein the putative β-cell or apopulation of putative β-cells are mature β-cells if the transcriptomeof the putative β-cell or the population of putative β-cells exhibits apattern of expression similar to the reference mature β-celltranscriptome.

In some aspects, the invention provides a method of distinguishingβ-cells and non-β-cells in a sample comprising pancreatic cells, themethod comprising: (a) obtaining a sample comprising pancreatic cells;(b) measuring expression of a plurality of genes in the sample toproduce a transcriptome of the pancreatic cells; (c) comparing thetranscriptome of the pancreatic cells to a reference β-celltranscriptome exhibiting a pattern of expression depicted in FIG. 12and/or a reference non-β-cell transcriptome exhibiting a pattern ofexpression depicted in FIG. 13; and (d) distinguishing β-cells and nonβ-cells, wherein (i) the pancreatic cells are β-cells if thetranscriptome of pancreatic cells exhibits a pattern of expressionsimilar to the reference β-cell transcriptome, or (ii) the pancreaticcells are non-β-cells if the transcriptome of pancreatic cells exhibitsa pattern of expression similar to the reference non-β-celltranscriptome.

In some aspects, the present invention provides a method of identifyingthe functional maturity of β-cells, the method comprising: (a) obtaininga putative β-cell or a population of putative β-cells; and (b) detectingan expression level in the putative β-cell or the population of putativeβ-cells of one or more genes listed in Table 2, Table 3 or Table 4,wherein: (i) an elevated level of expression of one or more genes listedin Table 1 or Table 2 in the putative β-cell or the population ofputative β-cells indicates that the putative β-cell or the population ofputative β-cells are functionally mature β-cells; and (ii) an elevatedlevel of expression of one or more genes listed in Table 3 or Table 4 inthe putative β-cell or the population of putative (3-cells indicatesthat the putative β-cell or the population of putative β-cells arefunctionally immature β-cells.

In some aspects, the present invention provides a method of identifyingmature β-cells, the method comprising: (a) obtaining a putative β-cellor a population of putative β-cells; and (b) detecting an expressionlevel in the putative β-cell or the population of putative β-cells ofone or more genes listed in Table 1 or Table 3, wherein: (i) an elevatedlevel of expression of one or more genes listed in Table 1 or Table 2 inthe putative β-cell or the population of putative β-cells indicates thatthe putative β-cell or the population of putative β-cells are matureβ-cells.

In some aspects, the present invention provides a method of identifyingfetal β-cells, comprising: (a) obtaining a putative β-cell or apopulation of putative β-cells; and

(b) detecting an expression level in the putative β-cell or thepopulation of putative (3 cells of one or more genes listed in Table 3,wherein: (i) an elevated level of expression of one or more genes listedin Table 3 in the putative β-cell or the population of putative β-cellsindicates that the putative β-cell or the population of putative β-cellsare fetal β-cells.

In some aspects, the present invention provides a method of identifyingin vitro-differentiated insulin-positive β-like cells, comprising: (a)obtaining a putative β-cell or a population of putative β-cells; and (b)detecting an expression level in the putative β-cell or the populationof putative β-cells of one or more genes listed in Table 4, wherein: (i)an elevated level of expression of one or more genes listed in Table 4in the putative β-cell or the population of putative β-cells indicatesthat the putative β-cell or the population of putative β-cells are invitro-differentiated insulin-positive β-like cells.

In some aspects, the present invention provides a method ofdistinguishing mature and immature β-cells, comprising: (a) obtaining aputative β-cell or a population of putative β-cells; (b) measuringexpression of a group of genes in the putative β-cell or the populationof putative β-cells to produce an expression profile of the β-cell orthe population of β-cells; (c) comparing the expression profile of theputative β-cell or the population of putative β-cells to any or all of:(i) a reference mature β-cell expression profile selected from the groupconsisting of a first group of genes having higher expression levels inmature β-cells compared to fetal β-cells, wherein the first group ofgenes is selected from the group consisting of STAT4, NPAS2, STAT3,NPAS2, STAT3, PBX3, NR3C2, DDIT3, SIX4, ETV5, SIX2, TP53, BCL6, MESP1,HOPX, BHLHB3, EPAS1, KLF9, KCNK3, GPI, CHGB, ALDOA, MAFA, SYT7, IAPP,WNT4, PDK3, KCNK1, SLC2A2, ESR1, G6PC2, and a second group of geneshaving higher expression levels in mature β-cells compared toinsulin-positive β-like cells, wherein the second group of genes isselected from the group consisting of XBP1, NFIA, PURA, PDX1, NR3C2,MNX1, GLIS3, EPAS1, HSF4, TSHZ3, MAFA, NKX6-1, HOPX, RORC, NFIX, PEG3,CEBPD, KLF9, STX1A, KCNMA1, PDX1, CHGB, MNX1, PCSK2, NKX6.1, GLIS3,KCNK12, KCNK3, GCGR, KCNK1, SLC30A8, PCSK1, MAFA, ESR1, SLC2A2, IAPP,G6PC2, STXBP1, KCNH2, KCNMB2, UCN3, WNT4; (ii) a reference immaturefetal β-cell expression profile selected from the group consisting of athird group of genes having higher expression levels in fetal β-cellscompared to mature β-cells, wherein said third group of genes isselected from the group consisting of LZTS1, EVI1, MYCN, FOS, EGR1,RCOR2, TCF3, ASCL2, NOTCH1, LMO4, PAX4, NFIB, ISX, SOX11, LHX4, ZNF423,SOX8, RFX1, PROX1, HHEX, CSRNP3, LZTR1, SOX4, NKX6.2, COL1A1, PAX4,KCNH6, RIMS3, PROX1, SOX4, ACSS1, GHRL, NOTCH1, KCNN3, GCK, PYY, HCN3,KCNJ4, and a fourth group of genes having higher expression levels ininsulin-positive β-like cells compared to mature β-cells, wherein saidfourth group of genes is selected from the group consisting of FOXA1,HHEX, NR2F1, FEV, IRX2, SOX11, PAX4, ONECUT2, LMO4, AEBP1, HES6, TGIF2,LZTS1, TCF3, GATA4, ARX, EGR1, RCOR2, CEBPA, ELF4, HNF4G, PBX2, ISX,ZNF217, NTS, GAST, RIMS3, CACNA1E, PYY, SCT, FOXA1, GATA4, KCNH6, ARX,DLL3, NOTCH1, IRX2, DPP4, PAX4, ACOX2, KCNB1, PROX1, GHRL, SLC2A1,ONECUT2, and SLC2A3; and (d) distinguishing mature and immature β-cells,wherein the putative β-cell or the population of putative β-cells are:(i) mature β-cells if the expression profile of the putative β-cell orthe population of putative β-cells exhibit a pattern of expressionsimilar to either reference mature β-cell expression profile; or (ii)immature β-cells if the expression profile of the putative β-cell or thepopulation of putative β-cells exhibit a pattern of expression similarto either reference immature β-cell expression profile expressionprofile.

In some aspects, the present invention provides a method ofdistinguishing mature and immature β-cells, comprising: (a) obtaining aputative β-cell or a population of putative β-cells; (b) assessingenrichment of a signaling pathway to produce a signaling pathwayenrichment plot of the putative β-cell or the population of putativeβ-cells, wherein the signaling pathway is selected from the groupconsisting of an unfolded protein response signaling pathway, an insulinsynthesis and secretion signaling pathway, and a metal ion SLCtransporters signaling pathway; and (c) distinguishing mature andimmature β-cells, wherein the putative β-cell or the population ofputative β-cells are: (i) mature β-cells if the signaling pathwayenrichment plot of the β-cell or the population of β-cells indicatesthat at least one of the unfolded protein response signaling pathway,the insulin synthesis and secretion signaling pathway, and the metal ionSLC transporters signaling pathway are enriched in the putative β-cellor the population of putative β-cells; or (ii) immature β-cells if thesignaling pathway enrichment plot of the β-cell or the population ofβ-cells indicates that none of the unfolded protein response signalingpathway, the insulin synthesis and secretion signaling pathway, and themetal ion SLC transporters signaling pathway are enriched in theputative β-cell or the population of putative β-cells.

In some aspects, the present invention provides a method ofdistinguishing mature and immature β-cells, comprising: (a) obtaining aputative β-cell or a population of putative β-cells; (b) assessingenrichment of a biological process to produce a biological processenrichment list of the putative β-cell or the population of putativeβ-cells, wherein the biological process is selected from the groupconsisting of: (i) generation of precursor metabolites and energy, (ii)oxidation reduction, (iii) vesicle-mediated transport, (iv) electrontransport chain, (v) monosaccharide metabolic process, (vi) cellmorphogenesis, (vii) cellular component morphogenesis, (viii) cellprojection organization, (ix) Wnt receptor signaling pathway, (x) cellprojection morphogenesis, (xi) cytoskeleton organization, (xii) sterolbiosynthetic process, (xiii) cholesterol biosynthetic process, (xiv)actin filament-based process, (xv) actin cytoskeleton organization,(xvi) sterol metabolic process, and (xvii) neuron projectiondevelopment; (c) distinguishing mature and immature β-cells, wherein theputative β-cell or the population of putative β-cells are: (i) matureβ-cells if the biological process enrichment list of the putative β-cellor the population of putative β-cells indicates that at least one of thebiological processes selected from the group consisting of (i), (ii),(iii), (iv), and (v) is enriched in the β-cell or the population ofβ-cells; or (ii) immature β-cells if the biological process enrichmentlist of the putative β-cell or the population of putative β-cellsindicates that at least one of the biological processes selected fromthe group consisting of (vi), (vii), (viii), (ix), (x), (xi), (xii),(xiii), (xiv), (xv), (xvi), and (xvii) is enriched in the putativeβ-cell or the population of putative β-cells.

In some aspects, the present invention provides a method of identifyinga candidate agent that modulates the functional maturity of β-cells,comprising: (a) contacting a β-cell or a population of β-cells with atest agent; (b) monitoring expression of a group of genes in the β-cellor the population of β-cells, in the presence of the test agent, toproduce an expression profile of the β-cell or the population ofβ-cells; (c) comparing the expression profile of the β-cell or thepopulation of β-cells to: (i) a reference mature β-cell expressionprofile selected from the group consisting of a first group of geneshaving higher expression levels in mature β-cells compared to fetalβ-cells, wherein the first group of genes is selected from the groupconsisting of KCNK3, GPI, CHGB, ALDOA, MAFA, SYT7, IAPP, WNT4, PDK3,KCNK1, SLC2A2, ESR1, G6PC2, and a second group of genes having higherexpression levels in mature β-cells compared to insulin-positive β-likecells, wherein the second group of genes is selected from the groupconsisting of STX1A, KCNMA1, PDX1, CHGB, MNX1, PCSK2, NKX6.1, GLIS3,KCNK12, KCNK3, GCGR, KCNK1, SLC30A8, PCSK1, MAFA, ESR1, SLC2A2, IAPP,G6PC2, STXBP1, KCNH2, KCNMB2, UCN3, and WNT4; (ii) a reference immatureβ-cell expression profile selected from the group consisting of a thirdgroup of genes having higher expression levels in fetal β-cells comparedto mature β-cells, wherein said third group of genes is selected fromthe group consisting of NKX6.2, COL1A1, PAX4, KCNH6, RIMS3, PROX1, SOX4,ACSS1, GHRL, NOTCH1, KCNN3, GCK, PYY, HCN3, and KCNJ4, and a fourthgroup of genes having higher expression levels in insulin-positiveβ-like cells compared to mature β-cells, wherein said fourth group ofgenes is selected from the group consisting of NTS, GAST, RIMS3,CACNA1E, PYY, SCT, FOXA1, GATA4, KCNH6, ARX, DLL3, NOTCH1, IRX2, DPP4,PAX4, ACOX2, KCNB1, PROX1, GHRL, SLC2A1, ONECUT2, and SLC2A3; and (d)identifying the test agent as a candidate agent that modulates thefunctional maturity of β-cells, wherein: (i) the test agent is acandidate agent that induces β-cells to become functionally mature ifthe β-cell or the population of β-cells exhibit a pattern of expressionsimilar to the either reference mature β-cell expression profile in thepresence of the test agent; (ii) the test agent is a candidate agentthat induces β-cells to become functionally immature if the β-cell orthe population of β-cells exhibit a pattern of expression similar toeither reference immature β-cell expression profile.

In some aspects, the present invention provides a method of identifyinga candidate agent that modulates the functional maturity of β-cells,comprising: (a) contacting a β-cell or a population of β-cells with atest agent; (b) assessing enrichment of a signaling pathway in thepresence of the test agent to produce a signaling pathway enrichmentplot of the β-cell or the population of β-cells, wherein the signalingpathway is selected from the group consisting of an unfolded proteinresponse signaling pathway, an insulin synthesis and secretion signalingpathway, and a metal ion SLC transporters signaling pathway; (c)identifying the test agent as a candidate agent that modulates thefunctional maturity of β-cells, wherein: (i) the test agent is acandidate agent that induces β-cells to become functionally mature ifthe signaling pathway enrichment plot of the β-cell or the population ofβ-cells indicates that at least one of the unfolded protein responsesignaling pathway, the insulin synthesis and secretion signalingpathway, and the metal ion SLC transporters signaling pathway areenriched in the β-cell or the population of β-cells; or (ii) the testagent is a candidate agent that induces β-cells to become functionallyimmature if the signaling pathway enrichment plot of the β-cell or thepopulation of β-cells indicates that none of the unfolded proteinresponse signaling pathway, the insulin synthesis and secretionsignaling pathway, and the metal ion SLC transporters signaling pathwayare enriched in the β-cell or the population of β-cells.

In some aspects, the present invention provides a method of identifyinga candidate agent that modulates the functional maturity of β-cells,comprising: (a) contacting a β-cell or a population of β-cells with atest agent; (b) assessing enrichment of a biological process in thepresence of the test agent to produce a biological process enrichmentlist of the β-cell or the population of β-cells, wherein the biologicalprocess is selected from the group consisting of (i) generation ofprecursor metabolites and energy, (ii) oxidation reduction, (iii)vesicle-mediated transport, (iv) electron transport chain, (v)monosaccharide metabolic process, (vi) cell morphogenesis, (vii)cellular component morphogenesis, (viii) cell projection organization,(ix) Wnt receptor signaling pathway, (x) cell projection morphogenesis,(xi) cytoskeleton organization, (xii) sterol biosynthetic process,(xiii) cholesterol biosynthetic process, (xiv) actin filament-basedprocess, (xv) actin cytoskeleton organization, (xvi) sterol metabolicprocess, and (xvii) neuron projection development; and (c) identifyingthe test agent as a candidate agent that modulates the functionalmaturity of β-cells, wherein: (i) the test agent is a candidate agentthat induces β-cells to become functionally mature if the biologicalprocess enrichment list of the β-cell or the population of β-cellsindicates that at least one biological process selected from the groupconsisting of (i), (ii), (iii), (iv), and (v) is enriched in the β-cellor the population of β-cells; or (ii) the test agent is a candidateagent that induces β-cells to become functionally immature if thebiological process enrichment list of the β-cell or the population ofβ-cells indicates that at least one biological process selected from thegroup consisting of (vi), (vii), (viii), (ix), (x), (xi), (xii), (xiii),(xiv), (xv), (xvi), and (xvii) is enriched in the β-cell or thepopulation of β-cells.

In some embodiments, the β-cell or the population of β-cells areobtained from an in vitro source. In some embodiments, the putativeβ-cell or the population of putative β-cells are obtained from an invitro source.

In some embodiments, the in vitro source is a culture of differentiatingstem cells.

In some embodiments, the stem cells are selected from the groupconsisting of human embryonic stem cells (hESCs), induced pluripotentstem cells (iPSCs), and combinations thereof. In some embodiments, thein vitro source is selected from the group consisting of a cell bank,cell line, cell culture, cell population, and combinations thereof. Insome embodiments, the in vitro source is an artificial tissue or organ.

In some embodiments, the cell or population of cells are obtained froman in vivo source. In some embodiments, β-cell or the population ofβ-cells are obtained from an in vivo source. In some embodiments, theputative β-cell or the population of putative β-cells are obtained froman in vivo source.

In some embodiments, the in vivo source is an individual that hasreceived an administration of β-cells. In some embodiments, the in vivosource is an individual suffering from a β-cell disorder selected fromthe group consisting of a disorder associated with immature β-cells, adisorder associated with destruction of β-cells, a disorder associatedwith dysfunctional β-cells, and a disorder associated with aninsufficient number of β-cells. In some embodiments, the in vivo sourceis an individual suspected of being in need of functionally matureβ-cells. In some embodiments, the in vivo source is a tissue or organobtained from a donor individual.

In some embodiments,the individual is a human or animal individual.

In some embodiments, measuring expression comprises utilizing atechnique selected from the group consisting of a microarray analysis,RNA-seq, RT-PCR, and q-RT-PCR.

In some embodiments, detecting the expression level comprises conductingat least one binding assay to determine the expression level of the oneor more genes.

In some embodiments, the methods further comprise sorting immature andmature β-cells. In some embodiments, sorting the immature and matureβ-cells fluorescence-activated cell sorting (FACS). In some embodiments,the FACS comprises staining at least one antibody specific for aputative β-cell surface marker selected from the group consisting ofABCA3, CD79B, FXYD2, KCNB2, NLGN1, PTPRU, SLC6A9, ABCC8, CD8A, GCGR,KCNF1, NPR2, ROBO1, SORL1, ABCG1, CDH2, GPR120, KCNG3, NRCAM, RTN4,SVOP, ACSL1, CDH22, GPR19, KCNH2, PCDHA1, SEMA5A, TGFBR3, ATP1B2,CHRNA5, GRIA2, KCNMA1, PCDHA3, SERP2, TRPM2, CACNA1H, CYB561, KCNH1,KCNQ2, PIGU, SLC17A6, TRPM5, CADM1, EFNB3, IGSF11, MADD, PLXNA2,SLC43A2, TSPAN13, CASR, FFAR1, IL17RB, NEO1, PRRG2, SLC6A6, and UNC5A.

In some embodiments, the methods further comprise quantifying the sortedβ-cells.

In some embodiments, the methods further comprise preserving the sortedβ-cells.

In some embodiments, the methods further comprise conducting a GSISassay on the β-cell or population of β-cells.

In some embodiments, the mature β-cell is a human β-cell.

In some embodiments, the fetal β-cell is a human β-cell.

In some embodiments, the insulin-positive β-like cell is derived fromhuman cells selected from the group consisting of human embryonic stemcells, reprogrammed human somatic cells, and induced human pluripotentstem cells.

In some aspects, the invention provides a method of delivering amolecule of interest to a β-cell or a population of β-cells, comprising:contacting the β-cell or the population of β-cells with a compositioncomprising the molecule of interest conjugated to an antibody that bindsto a putative β-cell surface marker selected from the group consistingof ABCA3, CD79B, FXYD2, KCNB2, NLGN1, PTPRU, SLC6A9, ABCC8, CD8A, GCGR,KCNF1, NPR2, ROBO1, SORL1, ABCG1, CDH2, GPR120, KCNG3, NRCAM, RTN4,SVOP, ACSL1, CDH22, GPR19, KCNH2, PCDHA1, SEMA5A, TGFBR3, ATP1B2,CHRNA5, GRIA2, KCNMA1, PCDHA3, SERP2, TRPM2, CACNA1H, CYB561, KCNH1,KCNQ2, PIGU, SLC17A6, TRPM5, CADM1, EFNB3, IGSF11, MADD, PLXNA2,SLC43A2, TSPAN13, CASR, FFAR1, IL17RB, NEO1, PRRG2, SLC6A6, and UNC5A.

In some aspects, the present invention provides a method of identifyinga candidate agent that modulates differentiation of β-cells, comprising:contacting a cell, population of cells, cell line or cell culture with atest agent; and monitoring the cell, population of cells, cell line, orcell culture for expression of one or more β-cell specific transcriptionfactors in the presence of the test agent, wherein the β-cell specifictranscription factors are selected from the group consisting of ASCL2,NR0B1, SIX4, CHD7, TOX, OLIG1, TSHZ3, DACH1, TSNAX, DACH2, MYT1L, PEG3,ZNF10, NDN, ZNF395, ETV5, ZNF540, HOPX, RXRG and ZNF672; and identifyingthe test agent as a candidate agent that modulates differentiation ofβ-cells if the cell, population of cells, cell line, or cell cultureexpresses one or more of the β-cell specific transcription factors inthe presence of the test agent.

In some aspects, the present invention provides a composition fordifferentiating a precursor cell to a pancreatic β-cell, comprising oneor more β-cell specific transcription factors selected from the groupconsisting of ASCL2, NR0B1, SIX4, CHD7, TOX, OLIG1, TSHZ3, DACH1, TSNAX,DACH2, MYT1L, PEG3, ZNF10, NDN, ZNF395, ETV5, ZNF540, HOPX, RXRG andZNF672.

In some aspects, the present invention provides a method fordifferentiating a precursor cell to a pancreatic β-cell, comprisingcausing the precursor cell to upregulate expression of one or moreβ-cell specific transcription factors selected from the group consistingof ASCL2, NR0B1, SIX4, CHD7, TOX, OLIG1, TSHZ3, DACH1, TSNAX, DACH2,MYT1L, PEG3, ZNF10, NDN, ZNF395, ETV5, ZNF540, HOPX, RXRG and ZNF672.

In some aspects, the present invention provides a method of detectingmature β-cells comprising conducting at least one binding assay for atleast one marker of β-cell functional maturity in a cell or a populationof cells, wherein the presence of the at least one marker of β-cellfunctional maturity in the cell or a population of cells indicates thatthe cell or population of cells are mature β-cells.

In some embodiments, the at least one marker of β-cell functionalmaturity is selected from the group consisting of the genes listed inTable 1 (Table 1A, Table 1B, or both Tables 1A and 1B) or Table 2 (Table2A, Table 2B, or both Tables 2A and 2B).

In some embodiments, the at least one marker of β-cell functionalmaturity comprises a protein marker of β-cell functional maturity.

In some embodiments, the at least one marker of β-cell functionalmaturity comprises an mRNA marker of β-cell functional maturity.

In some aspects, the present invention provides a method of detectingimmature β-cells comprising conducting at least one binding assay for atleast one marker of β-cell functional immaturity in a cell or populationof cells, wherein the presence of the at least one marker of β-cellfunctional immaturity in the cell or a population of cells indicatesthat the cell or population of cells are immature β-cells.

In some embodiments, the at least one marker of β-cell functionalimmaturity is selected from the group consisting of the genes listed inTable 3 (Table 3A, Table 3B, or both Tables 3A and 3B) or Table 4((Table 4A, Table 4B, or both Tables 4A and 4B).

In some embodiments, the at least one marker of β-cell functionalimmaturity comprises a protein marker of β-cell functional immaturity.

In some embodiments, the at least one marker of β-cell functionalimmaturity comprises an mRNA marker of β-cell functional immaturity.

BRIEF DESCRIPTION OF THE DRAWINGS

The patent or application file contains at least one drawing executed incolor. Copies of this patent or patent application publication withcolor drawings will be provided by the Office upon request and paymentof the necessary fee.

FIGS. 1A-1B depict an exemplary six stage directed differentiationprotocol. Cell types shown in FIG. 1A include: ES=embryonic stem cell;DE=definitive endoderm; PP=pancreatic progenitors; EP=endocrineprogenitors; EN=endocrine; Media components: Alk5i=a TGFβ signalinginhibitor that acts via inhibition of activin receptor-like kinase 5;FAF-BSA=fatty acid-free bovine serum albumin; KGF=keratinocyte growthfactor, also known as fibroblast growth factor 7; ITS-X=insulin,transferrin, selenium; noggin=a BMP signaling antagonist that acts viabinding of BMP-7; PDBu=phorbol 12,13-dibutyrate, a protein kinase Cagonist; RA=retinoic acid; SANT-1=a sonic hedgehog pathway antagonistthat acts via inhibition of the receptor smoothened. FIG. 1B depicts thestepwise differentiation from hESCs to pancreatic endocrine cells. TheTable shown in FIG. 1B contains reagents used during each stage ofdirected differentiation.

FIGS. 2A-2C demonstrate that human β-cells display a molecular signaturedistinct from other islet cells. FIG. 2A is a Table showing the resultsof a global analysis for probe sets differentially expressed (514 up,889 down) in human islet populations enriched for β-cells compared tothose depleted of β-cells. Human islet isolations likely containcontaminating non-islet tissues (e.g. exocrine cells, mesenchyme),contributing to the heterogeneity of the pool. Expression in unsortedislets is shown for comparison. Left, listed are the top ten geneontology terms for non-β islet cell-specific genes and alloverrepresented terms for β-cell-specific genes (q≤0.05). Right,row-normalized heatmap of probes shown with samples (columns) in theorder of human β-cells, other human islet cells, hESC-derived stage 6cells, and insulin+ stage 6 cells. From this list of probes, arraysignals are displayed for select established markers of non-β pancreaticcell types (FIG. 2B) and select known transcription factorspreferentially expressed in β-cells (FIG. 2C).

FIGS. 3A-3D demonstrate the results of protein analysis of sorted isletpopulations. FIG. 3A is a bar graph showing results obtained using theQproteome FFPE tissue kit; the inventors extracted a mean 104 pg proteinper cell, as determined by the micro BCA assay, from fixed human isletsand hESC-derived pancreatic cultures. Error bars are ±SEM. FIG. 3B is aschematic showing that Pdx1 protein of expected molecular weight wasresolved by SDS-PAGE and Western blot using lysate from hESC-derivedstage 6 cells that were paraformaldehyde-fixed and saponin-permeabilizedand from cells that were fresh/unfixed. FIG. 3C is a FACS plot depictinghuman islets dispersed, fixed, and stained for intracytoplasmic insulinand glucagon, resolving by FACS clear populations of β- and α-cells.FIG. 3D are schematics depicting Western blots of proteins isolated fromsorted β- and α-cells. Pdx1 was detected in β-cells but not α-cells,while glucokinase and the housekeeping protein Ran were equally found inβ- and α-cells.

FIGS. 4A-4D demonstrate global expression (GO) analysis of hESC-derivedcells and β-cells. FIGS. 4A-4D show gene ontology biological processannotation clustering for genes up-regulated in S6 insulin+ cellscompared to all unsorted S6 cells (2.6% of probes) (FIG. 4A), unsortedS6 cells compared to the S6 insulin+ population (2.3%) (FIG. 4B),β-cells compared to S6 insulin+ cells (4.0%) (FIG. 4C), and S6 insulin+cells compared to β-cells (4.9%) (FIG. 4D). Shown are the broadestenriched terms that are each representative of a cluster. Numbersindicate genes in each group with a given annotation.

FIGS. 5A-5C illustrate the relative expression of genes associated withendocrine pancreas development or function in β-cells and hESC-derivedcells. FIG. 5A is a heatmap showing normalized expression values of 71established endocrine lineage genes in human β-cells, hESC-derived stage6 (S6) cells fresh and unsorted, or S6 insulin+ cells. Of these genes,40 were significantly differentially expressed between the S6 insulin+cells and the unsorted population (FIG. 5B), and 35 were differentiallyexpressed between S6 insulin+ cells and human β-cells (FIG. 5C). Genesare listed by descending bio-weight.

FIGS. 6A-6D depict human β cell maturation. FIG. 6A shows FACS plots ofhuman adult islets and human fetal pancreata sorted for INS⁺ cells(APC⁺). FIG. 6B shows differentially expressed transcription factorsbetween adult and fetal β cells. FIG. 6C is a bar graph showing therelative expression of UCN3 in mouse and human fetal and adult β cells.Expression normalized to fetal levels in each species. FIG. 6D is aTable listing the top 5 most significant (Benjamini q value) Geneontology biological processes relatively enriched in either adult orfetal β cells.

FIGS. 7A-7D show the results of differential expression between human βcells and hPSC-derived insulin expressing cells. FIG. 7A is a Tablelisting 152 pancreatic lineage genes colored for genes that aredifferentially over-expressed in adult β cells (red) or hPSC-INS⁺ cells(blue). Differential gene expression was calculated based on microarraydata between human adult β cells and hPSC-INS⁺ cells (fold change >3,p<0.05) and confirmed by RNAseq between HUES8-INS⁺ cells and adult βcells (fold change >3). Asterisk indicates genes that are alsodifferentially expressed between fetal and adult β cells. FIG. 7B showsimmunofluorescence staining of hPSC-INS⁺ cells for PDX1, NKX6-1 andMAFA. Scale 100 um. FIG. 7C is alist of 42 transcription factors thatwere differentially expressed based on microarray data between humanadult β cells and hPSC-derived INS⁺ cells (fold change >3, p<0.05) andconfirmed by RNAseq between HUES8-INS⁺ cells and adult β cells (foldchange >3). FIG. 7D is a Table listing the top 10 most significant(Benjamini q value) gene ontology biological processes enrichedhPSC-INS⁺ cells over adult β cells.

FIGS. 8A-8C demonstrate a dysregulated ER stress response inhESC-derived insulin+ cells. FIG. 8A shows results of gene setenrichment analysis using curated Reactome gene sets identified threecanonical pathways significantly underexpressed in hESC-derived stage 6(S6) insulin+ cells compared to adult β-cells (FDR q-value<0.05).Enrichment plots are ordered from left to right by increasing q-value.FIG. 8B shows an Ingenuity Pathway Analysis (IPA) map of the endoplasmicreticulum stress pathway. All factors that overlapped with the Reactomeunfolded protein response pathway are shown. Members are colored suchthat green indicates underexpression in S6 insulin+ cells compared toβ-cells, and red indicates overexpression. Disease/function annotationsof pathway members are noted in ovals when relevant to β-cell biology.FIG. 8C is a schematic depicting genes downstream of XBP1 comprised themost significantly inhibited transcription factororiginated gene set inS6 insulin+ cells relative to β-cells. 28 of 34 differentially expressedgenes had expression direction consistent with XBP1 inhibition. Thep-value corresponds to the overlap between all underexpressed genes andthe genes regulated by XBP1, as determined in IPA. Asterisks indicatethat a gene is represented in the microarray by multiple probes.

FIGS. 9A-9C depict the expression of β-cell signature genes inhESC-derived cells. The signature gene sets of adult β-cells (458 genes)and non-β pancreatic cells (775 genes) identified in this study wereused to assess hESC-derived stage 6 (S6) cells. FIG. 9A shows that geneset enrichment analysis indicated significant enrichment of β-cell genesin S6 insulin+ cells compared to unsorted S6 cells (top panel), and ofnon-β pancreatic genes in unsorted S6 cells over the insulin+ fraction(middle panel). All genes were ranked by signal-to-noise ratio. p<0.001.FIG. 9B depicts hierarchical clustering based on Pearson correlationbetween centroids demonstrated that S6 insulin+ cells cluster moreclosely with β-cells than do unsorted S6 cells, but many differencesbetween S6 insulin+ cells and β-cells remain. A heatmap is shown withrow-normalized expression of all 1403 probes that comprise the signaturesets. FIG. 9C is a graph showing results of statistical weighted votingusing the 1403 probe signature classified unsorted S6 cells as non-βpancreatic cells with modest confidence, but S6 insulin+ cells could notbe confidently classified as β-cells. A positive confidence index(maximum 1.0) corresponds to expression similarity with the β-cellsignature compared to the non-β-cell signature. Bars are mean±SEM.

FIGS. 10A-10D depict β-cell signature transcription factor expression inhESC-derived insulin+ cells. FIG. 10A is a list of 49 transcriptionfactors within the signature set which were differentially expressed inS6 insulin+ cells compared to β-cells. Of the 20 factors having higherexpression levels in β-cells than S6 insulin+ cells, 18 are normallypreferentially expressed in β-cells. Genes are ordered by bioweight andexpression is displayed as fold change±SEM. FIGS. 10B-10D show theresults of immunohistochemistry, which revealed no co-expression ofNkx6.1 in c-peptide+ (insulin-producing) cells (FIG. 10B), littleco-expression of MafA (FIG. 10C), and full co-expression of Pdx1 (FIG.10D).

FIGS. 11A-11C demonstrate that hPSC-derived insulin expressing cellsresemble human fetal β cells. FIG. 11A is a bar graph showing glucosestimulated insulin secretion of dispersed cells. In contrast to adult βcells, fetal β cells and hPSC-INS⁺ cells both appear functionallyimmature as indicated by increased basal glucose secretion and lack ofglucose stimulation. FIG. 11B shows hierarchical clustering based onmicroarray global gene expression across all genes indicated thathPSC-INS⁺ cells cluster closely with human fetal and not adult β cells.Numbers in parentheses indicate biological replicates. Lengths in thedendrogram represent correlation distances. FIG. 11C shows R² valuesbased on microarray data across all genes are shown. Each row and columnrepresents one sample. R² values between biological replicates of adultβ cell samples (Adult_ins) are on average 0.89±0.04. R² values betweensorted hPSC-derived insulin⁺ stage 6 cells and sorted fetal β cells are0.88±0.02. The biological variation between adult β cells is notstatistically smaller then the variation between fetal β cells andhPSC-INS⁺ stage 6 cells (p=0.49). This indicates that a high degree ofsimilarity between hPSC-INS⁺ cells and human fetal β cells.

FIG. 12 shows a Table of genes with higher expression levels in sorted βcells relative to non β islet cells.

FIG. 13 shows a Table of genes with higher expression levels in non βislet cells relative to sorted β cells.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to novel markers for detecting β-cells(e.g., functionally mature β-cells), and methods of using those markersfor identifying functionally mature β-cells and distinguishing betweenimmature and mature β-cells (e.g., determining whether an invitro-differentiated β-cell has matured). In particular, the workdescribed herein provides for the first time the mature β-celltranscriptome. In addition, the work described herein provides geneswhich are differentially expressed between mature and immature β-cells,signaling pathways which are enriched in mature and immature β-cells,biological processes which are enriched in mature and immature β-cells,and putative β-cell cell-surface markers.

Accordingly, the present invention provides markers and methods foridentifying the functional maturity of β-cells (e.g., distinguishingbetween immature and mature β-cells in a population), identifying agentsthat modulate the functional maturity of a β-cell, identifying agentsthat modulate disorders associated with immature β-cells, identifyingindividuals in need of functionally mature β-cells, selectingfunctionally mature in vitro-differentiated β-cells or β-like cells foradministration to an individual (e.g., transplantation of mature β-cellsinto the individual, e.g., a human or animal), and identifying whetherβ-cells that have been administered to an individual are mature β-cellsin vivo.

In one aspect, the present invention provides a method of detectingmature β-cells. An exemplary method of detecting mature β-cellscomprises measuring expression of genes in a putative β-cell or apopulation of putative β-cells to produce a transcriptome of the β-cellor a population of β-cells, and comparing the transcriptome of theβ-cell or the population of β-cells to a reference mature β-celltranscriptome, wherein the β-cell or the population of β-cells aremature β-cells if the transcriptome of the β-cell or the population ofβ-cells exhibit a pattern of expression similar to the reference matureβ-cell transcriptome.

In some embodiments, a method of detecting mature β-cells comprises (a)obtaining a putative β-cell or a population of putative β-cells; (b)measuring expression of a plurality of genes in the β-cell or apopulation of β-cells to produce a transcriptome of the β-cell or thepopulation of β-cells; (c) comparing the transcriptome of the β-cell orthe population of β-cells to a reference mature β-cell transcriptomeexhibiting a pattern of expression depicted in FIG. 12; and (d)detecting mature β-cells, wherein the β-cell or the population ofβ-cells are mature β-cells if the transcriptome of the β-cell or thepopulation of β-cells exhibit a pattern of expression similar to thereference mature β-cell transcriptome.

In some aspects, the invention provides a method of distinguishingβ-cells and non-β-cells in a sample comprising pancreatic cells, themethod comprising: (a) obtaining a sample comprising pancreatic cells;(b) measuring expression of a plurality of genes in the sample toproduce a transcriptome of the pancreatic cells; (c) comparing thetranscriptome of the pancreatic cells to a reference β-celltranscriptome exhibiting a pattern of expression depicted in FIG. 12and/or a reference non-β-cell transcriptome exhibiting a pattern ofexpression depicted in FIG. 13; and (d) distinguishing β-cells and nonβ-cells, wherein (i) the pancreatic cells are β-cells if thetranscriptome of pancreatic cells exhibits a pattern of expressionsimilar to the reference β-cell transcriptome, or (ii) the pancreaticcells are non-β-cells if the transcriptome of pancreatic cells exhibitsa pattern of expression similar to the reference non-β-celltranscriptome.

The present invention contemplates the use of any suitable method tomeasure the expression of the genes in a putative β-cell or a populationof putative β-cells to produce a transcriptome. Other suitable methodswill be apparent to those skilled in the art. In some embodiments ofthis and other aspects of the invention, measuring expression comprisesutilizing a technique selected from the group consisting of a microarrayanalysis, RNA-seq, RT-PCR, and q-RT-PCR.

As used here, “transcriptome” refers to the collection of all genetranscripts in a and their appropriate relative abundances given cell(e.g., a β-cell), including both coding RNA (mRNAs) and non-coding RNAs(e.g., miRNA, tRNA, lincRNAs etc.).

In some embodiments the disclosure provides a mature β-celltranscriptome that may be used for a variety of purposes. In someembodiments the mature β-cell transcriptome comprises expression levelsof the genes listed in FIG. 12 or counterparts thereof (e.g., orthologsin other organisms). In some embodiments measurement of expressionlevels of the genes or a subset thereof may be used to identify matureβ-cells (e.g., as compared with immature β-cells, such as fetal β-cellsor in vitro-differentiated insulin-positive β-like cells). In someembodiments a subset comprises at least 5, 10, 20, 50, 100, 200, 300,400, or more genes listed in FIG. 12. Gene expression levels may bemeasured by measuring mRNA, protein or other gene product. Any suitablemethod may be used. In some embodiments gene expression may be measuredusing RNA-Seq, microarray analysis, or quantitative PCR. In someembodiments β-cells or populations of β-cells are classified based onthe mature β-cell transcriptome. For example, whether the β-cell's orβ-cell population's transcriptome more closely resembles a mature β-celltranscriptome or not may be determined. Heirarchical clustering or PCAanalysis may be used, for example, to determine whether a particularβ-cell population (e.g., colony, culture, cell line, etc.) clusters withmature β-cells as described herein or clusters with immature β-cells asdescribed herein. Mature β-cells which substantially match thetranscriptome of the mature β-cell transcriptome (e.g., that clusterwith mature β-cells as described herein), may, for example, be suitablefor administration in vivo. In some embodiments a mature β-celltranscriptome may be used in identifying compounds or conditions thatpromote formation of mature β-cells. For example, compounds orconditions may be used in a differentiation protocol and their effect onthe transcriptome of pluripotent cells subjected to the differentiationprotocol may be assessed. Compounds that promote a β-cell transcriptomeresembling that of a mature β-cell transcriptome may be identified. Suchcompounds may be used in a differentiation protocol to generate β-cells(e.g., functionally mature β-cells). In some embodiments, an R2correlation can be used to determine whether a cell is a β-cell. In suchembodiments, a cell is a β-cell when compared to the β-celltranscriptome gene expression data the cells have a correlationcoefficient (r) across all genes assessed r>0.9 or r>0.95 or r>0.98 orr>0.99.

As used herein, a “functionally immature β-cell” and “immature β-cell”are used interchangeably to refer to a cell that displays one or moremarkers of β-cell functional immaturity or does not display one or moremarkers of β-cell functional maturity, and lacks an appropriate GSISresponse.

As used herein, “marker of β-cell maturity” and “marker of functionalβ-cell maturity” are used interchangeably and refer to a mature β-celltranscriptome, one or more genes having higher expression levels inmature β-cells compared to fetal β-cells or in-vitro-differentiatedinsulin-positive β-like cells, one or more signaling pathways which areenriched in mature β-cells compared to fetal β-cells or invitro-differentiated insulin-positive β-like cells, or one or morebiological processes which are enriched in mature β-cells compared tofetal β-cells or in-vitro-differentiated insulin-positive β-like cells.

As used herein, a “marker of β-cell immaturity” and “marker offunctional β-cell immaturity” are used interchangeably to refer to oneor more genes having higher expression levels in fetal β-cells or invitro-differentiated insulin-positive β-like cells compared to matureβ-cells, one or more signaling pathways which are enriched in fetalβ-cells or in vitro-differentiated insulin-positive β-like cellscompared to mature β-cells, or one or more biological processes whichare enriched in fetal β-cells or in vitro-differentiatedinsulin-positive β-like cells compared to mature β-cells.

It is to be understood that the markers of β-cell maturity and markersof β-cell immaturity may be detectably expressed in the form of proteinand or mRNA within a cell. Accordingly, as used herein, “protein markerof β-cell maturity” and “protein marker of β-cell functional maturity”are used interchangeably to refer to a protein encoded by a gene whichis a marker of β-cell maturity. As used herein, “protein marker ofβ-cell immaturity” and “protein marker of β-cell functional immaturity”are used interchangeably to refer to a protein encoded by a gene whichis a marker of β-cell immaturity. As used herein, “mRNA marker of β-cellmaturity” and “mRNA marker of β-cell functional maturity” are usedinterchangeably to refer to mRNA encoded by a gene which is a marker ofβ-cell maturity. As used herein, “mRNA marker of β-cell immaturity” and“mRNA marker of β-cell functional immaturity” are used interchangeablyto refer to mRNA encoded by a gene which is a marker of β-cellimmaturity.

As used herein, a “functionally mature β-cell” and “mature β-cell” areused interchangeably to refer to a cell that displays one or moremarkers of β-cell functional maturity and exhibits an appropriate GSISresponse.

The markers and methods of the present invention are capable ofidentifying the functional maturity of any β-cell, β-like cell, orputative β-cell. As used herein “(3-like cell” refers to a cell thatdisplays at least two markers indicative of a pancreatic β-cell, suchas, pancreas duodenum homeobox-1 (PDX-1), insulin, somatostatin, glucosetransporter-2 (GLUT-2), glycogen, amylase, and neurogenin-3 (NGN-3), orgenes having higher expression levels in mature β-cells. Markersindicative of pancreatic β-cells also include morphologicalcharacteristics (e.g., spherical shape). As used herein“insulin-positive β-like cell” refers to a cell that displays the atleast two markers indicative of a pancreatic β-cell and also expressinsulin but lack an appropriate GSIS response. As used herein “invitro-differentiated insulin-positive β-like cell,” “S6 insulin+ cells,”“hPSC-ins+ cells,” HUE28-ins+ cells,” and “hESC-derived stage 6 (s6)insulin+ cells” are used interchangeably to refer to β-like cells thatare positive for insulin expression, and are derived fromdifferentiation of stem cells.

The markers and methods of the present invention are capable ofdistinguishing mature and immature β-cells. Generally, distinguishingbetween mature and immature β-cells can be accomplished by analyzingputative β-cell for one or more markers of β-cell functional maturity orone or more markers of β-cell functional immaturity. On the one hand, ifa putative β-cell or a population of putative β-cells displays one ormore markers of β-cell functional maturity, then the β-cell orpopulation of β-cells are likely mature β-cells. On the other hand, if aputative β-cell or a population of putative β-cells displays one or moremarkers of β-cell functional maturity, then the β-cell or population ofβ-cells are likely immature β-cells. Those skilled in the art willappreciate that confirmation of β-cell functional maturity or functionalimmaturity can be done by performing a GSIS assay to determine if theputative β-cell or the population of putative β-cells exhibits or lacksan appropriate GSIS response, respectively.

Genes Differentially Expressed Between Mature and Immature β-Cells

The present invention contemplates distinguishing mature and immatureβ-cells by detecting the presence or absence of expression of one ormore genes which are differentially expressed between mature andimmature β-cells in a β-cell, population of β-cells, a putative β-cell,or a population of putative β-cells.

In some aspects, the present invention provides a method of detectingmature β-cells, the method comprising conducting at least one bindingassay for at least one marker of β-cell functional maturity in a cell ora population of cells, wherein the presence of the at least one markerof β-cell functional maturity in the cell or a population of cellsindicates that the cell or population of cells are mature β-cells.

The present invention contemplates detecting mature β-cells by detectingthe presence of any marker of β-cell functional maturity in a cell or apopulation of cells. The cell or population of cells can be a cell orpopulation of cells suspected of being β-cells (e.g., a culturedifferentiating stem cells). In some embodiments, the at least onemarker of β-cell functional maturity is selected from the groupconsisting of the genes listed in Table 1 or Table 3. In someembodiments, the at least one marker of β-cell functional maturitycomprises a protein marker of β-cell functional maturity, as describedherein. In some embodiments, the at least one marker of β-cellfunctional maturity comprises an mRNA marker of β-cell functionalmaturity, as described herein.

In some aspects, the present invention provides a method of detectingimmature β-cells, the method comprising conducting at least one bindingassay for at least one marker of β-cell functional immaturity in a cellor population of cells, wherein the presence of the at least one markerof β-cell functional immaturity in the cell or a population of cellsindicates that the cell or population of cells are immature β-cells.

The present invention contemplates detecting immature β-cells bydetecting the presence of any marker of β-cell functional immaturity ina cell or a population of cells. The cell or population of cells can bea cell or population of cells suspected of being β-cells (e.g., aculture differentiating stem cells).

In some embodiments, the at least one marker of β-cell functionalimmaturity is selected from the group consisting of the genes listed inTable 3 or Table 4. In some embodiments, the at least one marker ofβ-cell functional immaturity comprises a protein marker of β-cellfunctional immaturity. In some embodiments, the at least one marker ofβ-cell functional immaturity comprises an mRNA marker of β-cellfunctional immaturity.

Generally, the presence of a protein marker of β-cell functionalmaturity in a β-cell or population of β-cells is indicative that theβ-cell or population of β-cells is functionally mature, whereas theabsence of the same protein marker in the β-cell or population ofβ-cells may be indicative that the β-cell or population of β-cells isfunctionally immature. Conversely, the presence of a protein marker ofβ-cell functional immaturity in a β-cell or population of β-cells isindicative that the β-cell or population of β-cells is functionallyimmature, whereas the absence of the same protein marker in the β-cellor population of β-cells may be indicative that the β-cell or populationof β-cells is functionally mature.

The present invention contemplates detecting the presence or absence ofprotein markers of β-cell functional maturity or immaturity according toany technique available to the skilled artisan. In some embodiments ofthis and other aspects of the invention, detecting the presence orabsence of protein markers of β-cell functional maturity or β-cellfunctional immaturity comprises immunostaining (e.g., Western blotting,immunohistochemistry, ELISA, etc). In such embodiments, anti-proteinmarker antibodies targeted to a particular protein marker of β-cellfunctional maturity or β-cell functional immaturity can be used todetect the presence or absence of the particular protein marker. For thepurposes of the invention the immunostaining techniques described ormentioned herein are considered binding assays.

Such antibodies can include polyclonal antibodies, monoclonalantibodies, chimeric antibodies, single-chain antibodies, antibodyfragments, humanized antibodies, multi-specific antibodies, and modifiedantibodies (e.g., fused to a protein to facilitate detection.) Suitableanti-marker protein antibodies can be generated according to routineprotocols, or can be readily obtained from a variety of commercialsources (e.g., Sigma-Aldrich). Other suitable techniques for detectingthe presence of proteins in β-cells are apparent to those skilled in theart.

Generally, the presence of elevated levels of mRNA markers of β-cellfunctional maturity in a β-cell or population of β-cells is indicativethat the β-cell or population of β-cells is functionally mature, whereasthe absence of the same mRNA markers (or relative lower levels of thesame mRNA markers) in the β-cell or population of β-cells may beindicative that the β-cell or population of β-cells is functionallyimmature. Conversely, the presence of elevated levels of mRNA markers ofβ-cell functional immaturity in a β-cell or population of β-cells isindicative that the β-cell or population of β-cells is functionallyimmature, whereas the absence of the same mRNA markers (or relativelower levels of the same mRNA markers) in the β-cell or population ofβ-cells may be indicative that the β-cell or population of β-cells isfunctionally mature.

It is to be understood that the phrase “elevated levels of mRNA” refersto levels of mRNA in a mature β-cell relative to an immature β-cell orlevels of mRNA in an immature β-cell relative to a mature β-cell.Elevated levels of mRNA may be represented as a fold-change inexpression of the mRNA in the mature β-cell relative to the immatureβ-cell, and vice versa.

The present invention contemplates detecting the presence or absence ofelevated levels of mRNA according to any technique available to theskilled artisan. In some embodiments of this and other aspects of theinvention, detecting the presence or absence of elevated levels of mRNAmarkers of β-cell functional maturity or immaturity in a β-cell orpopulation of β-cells comprises conducting one or more hybridizationassays. In some embodiments of this and other aspects of the invention,the one or more hybridization assays comprise a microarray. In someembodiments of this and other aspects of the invention, the one or morehybridization assay comprises RNA-seq. In some embodiments of this andother aspects of the invention, the one or more hybridization assayscomprises q-RT-PCR. For the purposes of the invention the hybridizationassays described or mentioned herein are considered binding assays.

In some embodiments of this and other aspects of the invention, thepresence of elevated levels of mRNA markers of β-cell functionalmaturity comprises at least a 2 fold increase, a 3 fold increase, a 4fold increase, a 5 fold increase, or N-fold increase (where N is apositive integer) in the levels of the mRNA marker in a mature β-cellrelative to the levels of the mRNA maker in immature β-cells.

In some embodiments of this and other aspects of the invention, thepresence of elevated levels of mRNA markers of β-cell functionalimmaturity comprises at least a 2 fold increase, a 3 fold increase, a 4fold increase, a 5 fold increase, or N-fold increase (where N is apositive integer) in the levels of the mRNA marker in an immature β-cellrelative to the levels of the mRNA marker in mature β-cells.

In some embodiments of this and other aspects of the invention, themarker of β-cell functional immaturity does not include PDX1. In someembodiments of this and other aspects of the invention, the marker ofβ-cell functional immaturity does not include MAFB. In some embodimentsof this and other aspects of the invention, the marker of β-cellfunctional immaturity does not include NKX6.1.

In some embodiments of this and other aspects of the invention, themarker of β-cell functional maturity does not include MAFA. In someembodiments of this and other aspects of the invention, the marker ofβ-cell functional maturity does not include NKX2.2. In some embodimentsof this and other aspects of the invention, the marker of β-cellfunctional maturity does not include UCN3.

In some aspects, a marker of β-cell functional maturity includes one,any combination or sub-combination, or all genes having a higherexpression level in mature β-cells compared to fetal β-cells or invitro-differentiated insulin-positive β-like cells.

Exemplary genes having higher expression levels in mature β-cellscompared to fetal β-cells are listed in Table 1 (Table 1 includes bothTable 1A and 1B).

TABLE 1A Genes with higher expression levels in mature β-cells comparedto fetal β-cells CHGB, IAPP, ESR1, HES1, SOX9, ALDOA, ATP6V0E1, GPI,PDK3, SYT4, G6PC2, SLC2A2, KCNK1, KCNK12, KCNK3, CDH2, WNT4, KLF9,EPAS1, BHLHB3, HOPX, MESP1, BCL6, TP53, SIX2, ETV5, SIX4, DDIT3, NR3C2,PBX3, STAT3, NPAS2, STAT4

TABLE 1B Genes with higher expression levels in mature β-cells comparedto fetal β-cells AADACL1, AARS, ABHD5, ABHD6, ABLIM1, ACAA2, ACAT1,ACBD3, ACSL1, ACTN1, ADCY9, ADIPOR1, ADM, ADSSL1, AFTPH, AGA, AGPAT9,AIDA, AIG1, AK2, AKT3, AKTIP, ALCAM, ALDH1L2, ALDOA, ALG5, ALKBH3, AMPH,AMZ2, ANGPTL2, ANKMY2, ANKRD12, ANKRD23, ANKRD40, ANKRD43, ANKRD57,ANTXR1, ANXA7, APITD1, APOA1BP, ARF4, ARHGEF3, ARL1, ARL8B, ARPC1A, ARX,AS3MT, ASNSD1, ATF1, ATG3, ATL1, ATP1B2, ATP6V0B, ATP6V0E1, ATP6V1D,ATP6V1E1, ATP6V1E2, ATP6V1G1, ATP6V1H, ATXN1, B2M, B3GNT6, B3GNT9, BAG3,BCL2L13, BCL2L2, BCL6, BEX2, BEX5, BHLHB2, BHLHB3, BMI1, BMP5, BOK,BOLA3, BPIL2, BRMS1, BRP44L, BTG3, BUD31, C10orf10, C10orf39, C11orf1,C11orf10, C11orf52, C11orf75, C12orf57, C12orf62, C13orf1, C13orf27,C14orf109, C14orf112, C14orf149, C14orf156, C14orf72, C15orf24,C15orf48, C15orf59, C16orf42, C16orf45, C17orf58, C17orf71, C17orf79,C18orf8, C19orf10, C19orf70, C1orf128, C1orf133, C1orf174, C1orf25,C1orf41, C1orf43, C1orf57, C1orf66, C1orf97, C21orf124, C21orf63,C22orf25, C2CD4B, C2orf28, C2orf30, C2orf32, C2orf42, C2orf7, C2orf76,C3orf14, C4orf34, C5orf32, C5orf53, C6orf64, C6orf89, C7orf23, C7orf30,C7orf42, C7orf52, C8orf40, C8orf59, C8orf76, C9orf103, C9orf119, C9orf9,C9orf91, CA5B, CAB39, CALCB, CAMK2N2, CAMTA1, CAPN13, CARS, CBX7,CCDC104, CCDC109B, CCDC28A, CCKBR, CCND3, CCNG1, CCPG1, CCT6B, CD2BP2,CD55, CD59, CD63, CD99, CD99L2, CDC14B, CDCP1, CDH18, CDH2, CDK5R2,CDKN1B, CDR2, CEBPG, CGRRF1, CHCHD10, CHCHD2, CHD5, CHDH, CHGB, CHPF,CHST1, CIB1, CKAP4, CLDN12, CLGN, CLIP4, CLN5, CMAS, CMBL, CMC1, CNIH4,CNPY2, CNRIP1, COPB1, COPS7A, COQ10A, COQ10B, COQ3, COX17, COX6B1,COX6C, COX7A1, COX7A2, COX7B, CPE, CPLX1, CPNE8, CRB3, CRY1, CRYZ, CSTB,CTBS, CTSL2, CUTC, CWC15, CXorf39, CXorf57, CYB561D1, CYB5R1, CYB5R4,CYP27A1, DAZAP2, DBI, DBNDD2, DCLRE1A, DCUN1D4, DDIT3, DEGS1, DGCR11,DGCR5, DHRS2, DHRS4, DHRS7B, DHX32, DIAPH1, DIRC2, DISP2,DKFZp686O24166, DKK4, DLG2, DMKN, DNAI1, DNAJB9, DNAJC12, DNAJC14,DNHD1, DNM3, DPM2, DPM3, DPYSL4, DRAM1, DUSP23, DYNC1I1, DYRK4, ECE2,EDEM1, EFHD1, EHBP1, EIF1AY, EIF2B3, EIF3I, EIF4E3, ELF1, ELMO1, ELMOD2,EMG1, ENAM, ENPP2, ENPP4, ENPP5, ENTPD3, EPAS1, EPB41L4B, EPDR1, EPSTI1,ERO1L, ERRFI1, ESYT1, ETFA, ETV5, EXOC5, EXOD1, F2RL1, FADS1, FAF1,FAM102A, FAM104A, FAM107A, FAM119B, FAM159B, FAM167A, FAM174A, FAM176A,FAM181B, FAM190B, FAM27A, FAM58A, FAM59A, FAM69A, FAM80A, FAM91A1,FAM96B, FAP, FBXL14, FBXL16, FBXO34, FBXO6, FBXO8, FHL1, FICD, FKBP11,FKBP2, FLJ20273, FLJ41603, FLJ43752, FLVCR2, FNDC3B, FOXN2, FRG1, FUCA1,FVT1, FYCO1, G3BP2, G6PC2, GABARAPL2, GAD1, GAD2, GAPDH, GARS, GAS2,GBE1, GC, GCNT3, GEM, GFPT1, GHDC, GHITM, GLO1, GLRB, GLRX, GLRX2, GLS2,GLT25D2, GLT8D2, GLTP, GMPR, GNE, GNPDA1, GOLGA4, GOLGA5, GOLPH3,GOLSYN, GOLT1A, GORASP2, GPI, GPM6A, GPR137B, GPR177, GPR19, GPR3, GPX3,GPX4, GRAMD1C, GREM2, GRIA3, GSN, GSTO1, GTF2E2, GTF2IRD1, GUCY1A3,GUCY1B3, GYG1, HABP4, HACL1, HAPLN4, HAX1, HDDC3, HELQ, HERC5, HERC6,HEXB, HINT1, HIVEP2, HLA-A29.1, HMGN4, HOPX, HPCAL4, HPRT1, HRASLS3,HS2ST1, HS6ST2, HSD17B12, HSPA4L, HSPA9, HSPC157, HSPC171, HTATIP2,IAH1, IAPP, ICAM2, IDI1, IER3, IER3IP1, IFI27L2, IFI35, IFI6, IFIH1,IFIT1, IFIT5, IFNAR2, IFNGR1, IFNGR2, IGFBP4, IL13RA1, IL17RB, IL20RA,INA, ING2, INPP1, INPP4B, INSIG2, IRAK2, IRAK4, IRS2, ISCU, ISG20L1,ITFG1, ITGA10, ITM2B, ITPR3, JAGN1, JAZF1, JPH3, JTB, KBTBD10, KCNF1,KCNJ16, KCNJ8, KCNK1, KCNK3, KCTD13, KCTD14, KCTD8, KDELR2, KIAA0247,KIAA0367, KIAA0408, KIAA0494, KIAA0672, KIAA1107, KIAA1128, KIAA1324,KIAA1644, KLF9, KLHDC8A, KLHL5, KPNA4, KPNA6, KRT222, LACTB2, LAMP1,LAMP2, LAMP3, LAPTM4B, LCMT2, LDLR, LDLRAP1, LGALS8, LGI2, LGI3, LHFPL4,LIMCH1, LIN7B, LIPL3, LMAN1, LMBRD1, LMNA, LMTK2, LOC100128353,LOC100128731, LOC100129673, LOC100129759, LOC100130633, LOC100131261,LOC100131531, LOC100131785, LOC100131801, LOC100133273, LOC100134537,LOC100144604, LOC133993, LOC145853, LOC147727, LOC154761, LOC203547,LOC283481, LOC284988, LOC285412, LOC387882, LOC388789, LOC389293,LOC389791, LOC390530, LOC391075, LOC391578, LOC399744, LOC400948,LOC440043, LOC440487, LOC440737, LOC440957, LOC442454, LOC643310,LOC643320, LOC643740, LOC644237, LOC644310, LOC644683, LOC644761,LOC645058, LOC645313, LOC645586, LOC645609, LOC646135, LOC646723,LOC646900, LOC647037, LOC647302, LOC647307, LOC648399, LOC648638,LOC648659, LOC649456, LOC650200, LOC650215, LOC650254, LOC650392,LOC650803, LOC651143, LOC652607, LOC652882, LOC653071, LOC653566,LOC727768, LOC728032, LOC728178, LOC728431, LOC728635, LOC729314,LOC729317, LOC729768, LOC731365, LOC732007, LOC732391, LOC88523, LPPR2,LRP10, LRP11, LRRC36, LRRFIP2, LSAMP, LSM1, LSM10, LSM3, LSMD1, LYPLAL1,LYRM1, LYSMD2, LZIC, MAD2L2, MAMDC2, MAN1A2, MAN1C1, MAN2B2, MANSC1,MAP1LC3B, MAP2K1IP1, MAP3K6, MAP6D1, MAPK9, MAPRE2, MARK1, MDH1, MDH2,ME1, MEA1, MEIS3, MEIS3P1, MESP1, METTL5, MFSD6, MGAT4A, MGC16291,MGST2, MGST3, MID2, MIR129-2, MKKS, MKRN2, MLF1, MMGT1, MMP1, MMP7,MOCS1, MOSC2, MPP5, MPV17, MR1, MRAP2, MRPL14, MRPE18, MRPL20, MRPL33,MRPL34, MRPL36, MRPL40, MRPL53, MRPS18C, MRPS23, MRPS28, MRPS33, MSI2,MST4, MT1X, MTCP1, MTHFD2, MTMR11, MTP18, MVP, MX1, MYL12A, MYO1D,MYOM1, N6AMT2, NAB1, NANS, NARS, NAT5, NBL1, NCALD, NCRNA00200, NDEL1,NDFIP1, NDUFA1, NDUFAB1, NDUFAF1, NDUFAF2, NDUFB3, NDUFB9, NDUFC1, NEBL,NEIL2, NEK1, NFE2L1, NFE2L2, NIPA1, NKIRAS1, NLF2, NLGN1, NLGN4Y, NMB,NMD3, NNMT, NOL3, NOL7, NOSTRIN, NPAS2, NPC1, NPM2, NPR2, NPTX2, NPY,NQO1, NQ02, NR0B1, NR2C2AP, NR3C2, NRD1, NUAK1, NUCB2, NUDT18, NUDT22,NUDT5, NUDT7, NUP88, OAT, OBFC1, OCEL1, OLFM1, OLIG1, OPTN, ORC3L,ORMDL2, OSBPL10, OSGIN2, OSTM1, OVOL2, OXCT2, OXGR1, P4HA2, PAK3, PALLD,PAM, PAPSS2, PARM1, PBX3, PCBP1, PCBP3, PCGF1, PCK1, PDE12, PDGFRL,PDK3, PDK4, PDLIM1, PDXK, PDZD8, PEA15, PEBP1, PELI1, PELO, PERP, PGAM1,PGCP, PGM1, PGM3, PGRMC2, PHF1, PHF11, PHF15, PHF17, PHF21B, PHLDA3,PIGH, PIGP, PIGT, PIGY, PIR, PITPNC1, PKIB, PLA2G4C, PLCB1, PLCL2, PLK2,PLOD2, PLS1, PNLIPRP2, PNMA2, PNPO, POLE3, POLR1D, PON3, PPA1, PPBP,PPCS, PPM1E, PPM1H, PPP1R1A, PPP1R3D, PPP2CB, PPP2R2C, PPP2R5A, PPP3CC,PPT1, PRAMEF19, PRDX1, PRDX4, PRICKLE4, PRKCA, PRNP, PROCR, PROS1,PROSC, PRR13, PRRT1, PRSS23, PRUNE2, PSMA6, PSMB1, PSMB4, PSMB6, PSMC3,PSMD8, PSMG1, PSMG2, PTGS2, PTPN11, PTPN3, PTPRN, PURA, PYROXD1, QPCT,RAB11FIP5, RAB1A, RAB21, RAB24, RAB2A, RAB31, RAB39B, RAB7A, RABAC1,RABGGTB, RABL3, RALYL, RAPH1, RASD1, RBBP8, RBM47, RCAN2, RCBTB2, REEP1,RFC4, RFESD, RGS17, RGS22, RGS4, RHEB, RICH2, RIN2, RIOK2, RIPPLY2,RLTPR, RNASEK, RNASEL, RNF130, RNF145, RNF181, RNF187, RPA3, RPH3AL,RPL26, RPL36AL, RPL41, RPP25, RPS19BP1, RPS27L, RQCD1, RSAD1, RSRC1,RTCD1, RTN4, SAMD3, SAMD4B, SAT2, SBDS, SC5DL, SCG2, SCG3, SCG5,SCGB2A1, SDC2, SDC4, SDF2, SDF2L1, SDHB, SDSL, SEC11C, SEC22A, SEC22B,SEC61B, SEC61G, SEL1L3, SELK, SELM, SEMA5A, SEPHS2, SEPW1, SERF2,SERINC1, SERINC3, SERPINB1, SERTAD4, SESN1, SEZ6L, SFMBT1, SFT2D1, SGCE,SGIP1, SGK3, SGMS2, SH3GLB1, SIPA1L2, SIX2, SIX4, SLBP, SLC12A8,SLC17A6, SLC1A4, SLC25A4, SLC2A10, SLC2A12, SLC2A13, SLC31A2, SLC35A5,SLC35D3, SLC35F3, SLC39A1, SLC39A8, SLC41A1, SLC45A3, SLC46A3, SLC6A17,SLC6A6, SLC7A1, SLC7A5, SLC8A2, SLC8A3, SMAP1, SMPDL3A, SNAP91, SNCB,SNPH, SNRPG, SOD1, SORL1, SPATA18, SPCS1, SPCS2, SPCS3, SPG3A, SPIRE1,SPPL2A, SPR, SPTBN4, SQSTM1, SRD5A1, SRP54, SRPRB, SRXN1, STAMBPL1,STAT3, STAT4, STEAP2, STIM1, STXBP5, STXBP6, STYXL1, SUCLG2, SUMO3,SURF1, SURF2, SUSD4, SYNGR3, SYNGR4, SYPL1, SYS1, SYT13, SYT4, T1560,TACC1, TAF12, TANC2, TAP1, TARS, TAX1BP1, TBC1D15, TBC1D22A, TBC1D8,TBC1D8B, TBCA, TCEAL2, TCEAL3, TCEAL6, TCEB1, TDRD7, TGFBR3, THEM2,THOC7, TICAM2, TIMM10, TIMP2, TM9SF2, TMBIM1, TMBIM6, TMCO3, TMCO4,TMED10P, TMED2, TMED3, TMED7, TMEM106C, TMEM109, TMEM111, TMEM116,TMEM126B, TMEM130, TMEM133, TMEM144, TMEM147, TMEM14A, TMEM14B, TMEM14D,TMEM163, TMEM166, TMEM167A, TMEM167B, TMEM208, TMEM219, TMEM27, TMEM30B,TMEM38B, TMEM4, TMEM54, TMEM59, TMEM60, TMEM66, TMEM70, TMEM99, TMOD1,TncRNA, TNFRSF11A, TNFRSF21, TOMM5, TOMM7, TP53, TRAM1, TRAPPC2P1,TRAPPC4, TSGA14, TSHZ3, TSPAN13, TSTD1, TTC1, TTC39B, TTC39C, TUFT1,TXN, TXNDC11, TXNDC17, TXNDC9, TXNL1, UAP1L1, UBA5, UBE2D3, UBE2D4,UBE2E2, UBL3, UBTD1, UCHL5, UFM1, UFSP2, UGDH, UNC50, UNC5CL, UQCRB,UQCRQ, USO1, UTP11L, VAMP2, VAMP4, VAV3, VCPIP1, VGF, VLDLR, VPS37A,VPS37C, VTI1B, VWA5A, WAC, WASL, WBSCR27, WDR25, WDR5B, WDYHV1, WNT4,WSB2, WWC1, XBP1, YARS, ZC3H12C, ZCWPW2, ZMYM6, ZNF143, ZNF226, ZNF252,ZNF331, ZNF385D, ZNF395, ZNF540, ZNF83, ZNFX1

It is to be understood that the levels of expression of one or more ofthe genes listed in Table 1 are depicted in FIG. 6C as a fold change inexpression of mature β-cells compared to fetal β-cells.

It should also be appreciated that any gene listed in Table 1 can beused as a marker for detecting mature β-cells by measuring the level ofexpression of the gene in a cell, culture, cell line, tissue, orpopulation of cells (e.g., suspected of being β-cells), wherein if thelevel of expression of the gene in the cell, culture, cell line, tissue,or population of cells is elevated (for example, as depicted in FIG.6C), the cell, culture, cell line, tissue, or population of cellscomprises mature β-cells.

Those skilled in the art will also appreciate that any two or more ofthe genes listed in Table 1 can be used in combinations of up to N genes(where N is a positive integer greater than or equal to 2) as markersfor detecting mature β-cells by measuring the levels of expression ofthe combination of genes in a cell, culture, cell line, tissue, orpopulation of cells (e.g., suspected of being β-cells), wherein if thelevels of expression of the combination of genes in the cell, culture,cell line, tissue, or population of cells is elevated (for example, asdepicted in FIG. 6C), the cell, culture, cell line, tissue, orpopulation of cells comprises mature β-cells.

Exemplary genes which have higher expression levels in mature β-cellscompared to in vitro-differentiated insulin-positive β-like cells arelisted in Table 2 (Table 2 includes both Tables 2A and 2B).

TABLE 2A Genes with higher expression levels in mature β-cells comparedto in vitro-differentiated insulin-positive β-like cells KLF9, CEBPD,PEG3, NFIX, RORC, HOPX, TSHZ3, HSF4, EPAS1, GLIS3, NR3C2, SIX4, PURA,NFIA, XBP1, CHGB, IAPP, ESR1, GLIS3, MAFA, MNX1, NKX6-1, PDX1, GPI,PCSK1, PCSK2, SLC30A8, STX1A, STXBP1, SYT4, G6PC2, SLC2A2, KCNA5, KCNH2,KCNK1, KCNK12, KCNK3, KCNMA1, GCGR, UCN3, WNT4

TABLE 2B Genes with higher expression levels in mature β-cells comparedto in vitro-differentiated insulin-positive β-like cells A2LD1, A2M,A4GNT, AADAC, AADACL1, AAED1, AANAT, AARS, AARSD1, AASDH, AB019439.68,AB019441.29, ABCA10, ABCA13, ABCA17P, ABCA5, ABCA6, ABCA8, ABCA9,ABCA9-AS1, ABCB1, ABCB10P1, ABCB10P4, ABCB11, ABCB7, ABCC12, ABCC2,ABCC3, ABCC9, ABCD2, ABCE1, ABCG1, ABCG8, ABHD1, ABHD10, ABHD11-AS1,ABHD2, ABHD3, ABHD5, ABHD6, ABI3, ABP1, ABRACL, AC000036.4, AC000110.1,AC000124.1, AC002056.3, AC002056.5, AC002064.5, AC002128.4, AC002306.1,AC002310.10, AC002314.2, AC002398.12, AC002398.9, AC002400.1,AC002429.5, AC002456.2, AC002467.5, AC002486.2, AC002511.2, AC002511.4,AC002519.5, AC002519.6, AC002553.1, AC003087.4, AC003092.2, AC003101.1,AC003104.1, AC003989.3, AC003991.3, AC004014.4, AC004019.10, AC004041.2,AC004069.2, AC004074.3, AC004156.3, AC004159.1, AC004240.2, AC004381.7,AC004383.3, AC004461.4, AC004471.9, AC004485.3, AC004528.4, AC004562.1,AC004696.2, AC004744.3, AC004771.1, AC004797.1, AC004832.1, AC004837.5,AC004840.8, AC004851.1, AC004854.4, AC004854.5, AC004870.5, AC004876.1,AC004878.7, AC004899.3, AC004941.3, AC004945.1, AC004988.1, AC005027.3,AC005037.1, AC005062.2, AC005076.5, AC005077.8, AC005082.12, AC005102.1,AC005229.1, AC005255.1, AC005262.4, AC005264.2, AC005280.1, AC005281.2,AC005307.1, AC005307.3, AC005336.2, AC005336.5, AC005351.1, AC005355.1,AC005356.1, AC005391.2, AC005481.5, AC005498.3, AC005517.3, AC005532.5,AC005534.9, AC005546.2, AC005616.2, AC005682.7, AC005740.3, AC005779.2,AC005783.1, AC005884.1, AC005895.3, AC006001.1, AC006019.3, AC006019.4,AC006026.10, AC006026.13, AC006026.9, AC006033.22, AC006038.4,AC006042.8, AC006070.11, AC006116.12, AC006116.13, AC006116.15,AC006116.17, AC006116.21, AC006116.24, AC006116.26, AC006157.2,AC006227.1, AC006296.3, AC006355.3, AC006369.2, AC006378.2, AC006378.3,AC006460.2, AC006465.3, AC006483.5, AC006486.1, AC006509.7, AC006539.1,AC006946.12, AC007000.11, AC007009.1, AC007009.2, AC007014.1,AC007041.2, AC007098.1, AC007099.2, AC007126.1, AC007204.2, AC007229.3,AC007246.3, AC007249.3, AC007253.1, AC007255.7, AC007255.8, AC007271.3,AC007272.3, AC007277.3, AC007279.2, AC007282.6, AC007283.4, AC007283.5,AC007318.5, AC007319.1, AC007349.5, AC007362.1, AC007362.3, AC007365.3,AC007386.3, AC007386.4, AC007389.4, AC007390.5, AC007390.6, AC007392.3,AC007392.4, AC007405.2, AC007567.1, AC007618.3, AC007620.3, AC007682.1,AC007731.1, AC007750.5, AC007787.2, AC007796.1, AC007842.2, AC007879.2,AC007879.4, AC007879.5, AC007881.1, AC007919.18, AC007952.1, AC007966.1,AC007970.1, AC008069.2, AC008132.12, AC008147.2, AC008155.1, AC008269.2,AC008279.1, AC008280.3, AC008427.2, AC008537.2, AC008555.2, AC008581.1,AC008592.3, AC008592.4, AC008592.5, AC008703.1, AC008746.5, AC008937.2,AC008937.3, AC008984.7, AC008992.2, AC009093.1, AC009095.4, AC009120.10,AC009120.4, AC009166.5, AC009223.1, AC009232.2, AC009236.1, AC009236.2,AC009237.1, AC009237.11, AC009237.8, AC009274.6, AC009299.2, AC009299.3,AC009302.2, AC009303.1, AC009475.2, AC009487.6, AC009495.3, AC009495.4,AC009499.1, AC009501.4, AC009502.1, AC009506.1, AC009948.5, AC009948.7,AC009950.2, AC009961.5, AC009963.6, AC009994.2, AC010095.5, AC010127.4,AC010136.2, AC010149.4, AC010226.4, AC010240.2, AC010240.3, AC010336.2,AC010468.1, AC010487.1, AC010525.4, AC010525.5, AC010525.7, AC010547.9,AC010641.1, AC010733.4, AC010878.3, AC010890.1, AC010894.5, AC010969.1,AC010982.1, AC011239.1, AC011242.6, AC011290.5, AC011298.2, AC011322.1,AC011330.12, AC011330.5, AC011330.6, AC011385.1, AC011406.2, AC011450.2,AC011477.1, AC011498.1, AC011499.1, AC011526.1, AC011537.1, AC011754.1,AC011816.3, AC011891.5, AC011933.2, AC012065.5, AC012066.1, AC012074.2,AC012087.2, AC012146.7, AC012309.5, AC012314.6, AC012317.1, AC012354.6,AC012354.8, AC012360.4, AC012363.4, AC012442.5, AC012512.1, AC013268.5,AC013269.3, AC013275.2, AC013468.1, AC013470.6, AC013717.3, AC013733.3,AC015726.1, AC015849.14, AC015922.6, AC015922.7, AC015923.1, AC015971.2,AC015987.1, AC015987.2, AC016292.3, AC016582.2, AC016586.1, AC016644.1,AC016689.1, AC016700.3, AC016700.4, AC016700.6, AC016716.1, AC016732.2,AC016745.1, AC016831.7, AC016909.1, AC016910.1, AC016912.3, AC016995.3,AC017048.3, AC017048.4, AC017071.1, AC017074.1, AC017079.3, AC017079.4,AC017083.2, AC017083.3, AC017101.10, AC017104.2, AC017104.4, AC018462.2,AC018642.1, AC018696.4, AC018696.7, AC018720.10, AC018735.1, AC018737.1,AC018737.4, AC018867.2, AC018890.6, AC019050.1, AC019097.7, AC019117.2,AC019181.3, AC019186.1, AC019294.1, AC020571.3, AC020594.5, AC020900.2,AC020907.1, AC022153.1, AC022182.3, AC022431.1, AC022819.3, AC023085.1,AC023797.1, AC024082.3, AC024560.2, AC024592.9, AC024704.2, AC025287.1,AC025335.1, AC025442.3, AC025750.6, AC025918.2, AC026150.6, AC026150.9,AC026166.1, AC026202.3, AC026471.6, AC034110.1, AC034154.1, AC034187.2,AC034228.4, AC034229.1, AC037459.4, AC044860.1, AC046130.1, AC053503.4,AC055811.1, AC058791.2, AC060226.1, AC062028.1, AC062029.1, AC063976.3,AC063976.6, AC064843.1, AC064843.2, AC064850.4, AC064871.3, AC064872.1,AC066692.3, AC067945.4, AC067950.1, AC067961.1, AC068042.1, AC068134.6,AC068134.8, AC068137.2, AC068279.3, AC068491.1, AC068491.3, AC068492.1,AC068538.2, AC068754.1, AC069154.2, AC069155.1, AC069200.1, AC069282.6,AC069292.6, AC069363.1, AC072031.1, AC073043.2, AC073072.5, AC073109.2,AC073115.7, AC073128.10, AC073135.2, AC073254.1, AC073316.1, AC073343.1,AC073343.11, AC073343.2, AC073410.1, AC073479.1, AC073626.2, AC073635.5,AC073834.3, AC073842.18, AC073842.19, AC073934.6, AC074011.2,AC074091.1, AC074091.13, AC074182.1, AC074183.4, AC074212.3, AC074391.1,AC078819.1, AC078852.1, AC078852.2, AC078883.4, AC078899.1, AC079140.1,AC079145.4, AC079250.1, AC079354.6, AC079466.1, AC079630.4, AC079741.2,AC079922.3, AC083799.1, AC083843.3, AC083862.1, AC083863.7, AC083873.4,AC083899.3, AC083900.1, AC084125.2, AC084149.1, AC084809.3, AC084859.1,AC087163.2, AC087294.2, AC087501.1, AC087793.1, AC090044.1, AC090044.2,AC090286.2, AC090286.4, AC090420.1, AC090519.7, AC090587.4, AC090602.1,AC090617.1, AC090952.4, AC091167.3, AC091492.2, AC091633.2, AC091729.7,AC091729.8, AC091969.1, AC092106.2, AC092117.1, AC092155.1, AC092165.4,AC092170.1, AC092295.4, AC092574.1, AC092574.2, AC092594.1, AC092597.3,AC092610.12, AC092646.2, AC092661.2, AC092664.1, AC092667.2, AC092687.5,AC092755.4, AC092811.1, AC092835.2, AC093106.7, AC093142.2, AC093162.5,AC093171.1, AC093390.1, AC093391.2, AC093510.1, AC093620.5, AC093627.12,AC093662.6, AC093702.1, AC093899.3, AC094019.4, AC096579.1, AC096591.1,AC096649.1, AC096649.2, AC096669.1, AC096669.3, AC096670.3, AC096753.1,AC096753.2, AC097359.1, AC097381.1, AC097382.1, AC097467.2, AC097500.1,AC097500.2, AC097523.1, AC097523.2, AC097635.5, AC097662.2, AC097711.1,AC097721.2, AC097724.3, AC098592.6, AC098614.2, AC098820.3, AC098823.3,AC098828.3, AC099048.1, AC099344.3, AC099535.4, AC099544.2, AC099552.4,AC099850.1, AC100803.1, AC103681.1, AC103740.1, AC103801.2, AC104024.1,AC104076.3, AC104134.2, AC104135.2, AC104297.1, AC104306.1, AC104306.2,AC104306.4, AC104600.1, AC104650.2, AC104651.2, AC104695.3, AC104841.1,AC104984.4, AC104986.1, AC105020.1, AC105052.2, AC105053.4, AC105247.1,AC105396.3, AC105399.2, AC105402.1, AC105402.4, AC105461.1, AC106053.1,AC106722.1, AC106827.2, AC107021.1, AC107072.2, AC107081.5, AC107982.4,AC108039.1, AC108066.1, AC108448.2, AC108463.1, AC108463.2, AC108463.3,AC108488.3, AC108676.1, AC108868.3, AC108868.4, AC108938.2, AC109309.4,AC109309.5, AC109826.1, AC109826.2, AC110491.1, AC111200.2, AC112229.7,AC113554.1, AC113607.1, AC113607.2, AC113607.3, AC114546.1, AC114730.2,AC114730.3, AC114730.5, AC114752.2, AC114755.3, AC114772.1, AC114776.1,AC114947.1, AC116050.1, AC116366.5, AC117490.2, AC117834.1, AC118344.1,AC120194.1, AC121336.1, AC121336.2, AC123768.3, AC123886.2, AC124890.1,AC126118.1, AC128709.1, AC129492.6, AC131011.1, AC131097.4, AC133485.1,AC133644.3, AC135776.1, AC136289.1, AC137590.1, AC137932.6, AC138430.2,AC138430.4, AC138655.4, AC138783.12, AC138972.1, AC139099.3, AC139099.5,AC139099.6, AC139452.2, AC139712.2, AC140061.1, AC140061.11, AC140481.2,AC140481.4, AC140481.7, AC140481.8, AC140481.9, AC144521.1, AC144835.1,AC145124.2, AC145291.1, AC145343.2, AC145676.2, AC147651.4, AC147651.5,AC156455.1, AC195454.1, AC226119.1, AC226119.4, ACA59, ACA64, ACACB,ACAD11, ACADM, ACADSB, ACAP2, ACAT1, ACBD3, ACBD5, ACCSL, ACE2, ACLY,ACMSD, ACN9, ACOT12, ACOT13, ACOT4, ACOT6, ACOXL, ACPP, ACRBP, ACRC,ACRV1, ACSBG1, ACSBG2, ACSL1, ACSL3, ACSL4, ACSL5, ACSL6, ACSM1, ACSM5,ACSS1, ACTA1, ACTBP1, ACTBP11, ACTBP7, ACTBP9, ACTC1, ACTG1, ACTG1P10,ACTN2, ACTR10, ACTR3B, ACTR6, ACYP1, AD000091.3, AD001527.5, ADAL,ADAM17, ADAM1B, ADAM20, ADAM20P1, ADAM21, ADAM24P, ADAM28, ADAM29,ADAM9, ADAMDEC1, ADAMTS4, ADAMTS5, ADAMTSL2, ADAP2, ADCY3, ADCYAP1,ADH1C, ADH5P2, ADK, ADM, ADO, ADORA2BP, ADORA3, ADPRM, ADRA1D, ADRA2A,ADRB2, ADSS, ADTRP, AE000661.37, AEBP2, AF001548.5, AF011889.2,AF038458.4, AF064858.8, AF064860.7, AF124730.4, AF127577.1, AF127577.10,AF127577.8, AF130249.5, AF131215.1, AF131215.5, AF131215.6, AF186192.1,AF186192.5, AF186192.6, AF196972.4, AF196972.9, AF207550.1, AF213884.2,AF228730.12, AF228730.7, AF230666.2, AFF1, AFF4, AFTPH, AGAP10, AGBL3,AGGF1, AGMO, AGPAT9, AGPHD1, AGRP, AGTPBP1, AGXT2L1, AHCTF1, AHCYL1,AHI1, AHNAK2, AHRR, AIDA, AIG1, AIG1P1, AIMP1, AIRE, AK2, AK2P2, AKAP11,AKAP14, AKAP2, AKAP3, AKAP6, AKAP7, AKNAD1, AKR1B10, AKR1C3, AKR1CL1,AKT3, AKT3-IT1, AL022393.7, AL023807.1, AL031601.3, AL031602.1,AL031768.1, AL049757.3, AL050327.1, AL078621.11, AL078621.13,AL078621.3, AL078633.1, AL109615.1, AL109761.5, AL109767.1, AL109806.1,AL132709.1, AL132709.2, AL132709.5, AL132709.8, AL135791.1, AL136419.1,AL136985.1, AL137127.1, AL137229.1, AL137855.1, AL138479.3, AL138706.1,AL138795.1, AL138796.1, AL138968.1, AL139099.1, AL139239.1, AL139333.1,AL139377.1, AL157788.1, AL159997.1, AL160275.1, AL160314.1, AL161645.1,AL161645.2, AL161793.1, AL162389.1, AL162431.1, AL353626.1, AL353626.2,AL353629.1, AL353662.3, AL353671.1, AL353997.7, AL358175.1, AL358175.2,AL359218.1, AL359314.1, AL359392.1, AL359473.1, AL359736.1, AL359955.1,AL360004.1, AL360297.1, AL390071.1, AL390877.1, AL391152.1, AL441988.1,AL512652.1, AL512791.1, AL589743.1, AL590113.1, AL590226.1, AL590431.1,AL590703.1, AL590762.6, AL590762.7, AL590764.1, AL590787.1, AL591516.1,AL591516.2, AL591516.3, AL591516.4, AL591704.5, AL591893.1, AL592494.1,AL592494.3, AL592494.5, AL645730.2, AL672294.1, AL691479.1, AL773572.7,AL773604.8, ALAS2, ALCAM, ALDH1A2, ALDH1A3, ALDH1L1-AS1, ALDH1L2,ALDH9A1, ALDOB, ALG10, ALG10B, ALG11, ALG13-AS1, ALG14, ALG2, ALG5,ALG8, ALG9, ALKBH1, ALKBH3, ALMS1, ALOX12P1, ALOX5, ALOXE3, ALS2CL,ALS2CR12, ALS2CR8, ALX1, AMBN, AMD1, AMIGO3, AMMECR1, AMMECR1LP1, AMN1,AMPD1, AMPD3, AMY2A, AMZ2, AMZ2P1, ANAPC10, ANAPC10P1, ANAPC13, ANAPC16,ANAPC4, ANGEL1, ANGPT4, ANGPTL1, ANGPTL2, ANGPTL3, ANGPTL4, ANGPTL5,ANGPTL6, ANGPTL7, ANKAR, ANKDD1B, ANKH, ANKHD1, ANKMY2, ANKRD12,ANKRD13C, ANKRD16, ANKRD18EP, ANKRD2, ANKRD20A1, ANKRD20A14P,ANKRD20A19P, ANKRD20A2, ANKRD20A3, ANKRD20A5P, ANKRD22, ANKRD23,ANKRD26P1, ANKRD26P4, ANKRD27, ANKRD29, ANKRD30A, ANKRD31, ANKRD32,ANKRD33, ANKRD33B, ANKRD34C, ANKRD36BP1, ANKRD36BP2, ANKRD37, ANKRD40,ANKRD42, ANKRD43, ANKRD45, ANKRD5, ANKRD6, ANKRD62, ANKRD7, ANO5,ANP32BP1, ANP32C, ANP32E, ANTXR1, ANXA11, ANXA2, ANXA2P2, ANXA2P3,ANXA5, ANXA7, AP000233.3, AP000253.1, AP000282.2, AP000304.2,AP000354.2, AP000356.1, AP000432.2, AP000435.1, AP000442.1, AP000462.1,AP000462.2, AP000473.5, AP000525.1, AP000525.8, AP000552.1, AP000568.2,AP000580.1, AP000593.5, AP000593.6, AP000593.7, AP000648.6, AP000662.9,AP000695.4, AP000695.6, AP000705.7, AP000769.1, AP000790.1, AP000797.2,AP000797.4, AP000807.2, AP000925.2, AP000936.2, AP000974.1, AP001007.1,AP001010.1, AP001042.1, AP001044.2, AP001046.5, AP001052.9, AP001053.11,AP001059.5, AP001062.9, AP001065.2, AP001187.9, AP001189.4, AP001205.1,AP001324.1, AP001372.2, AP001432.14, AP001469.7, AP001596.6, AP001597.1,AP001607.1, AP001610.5, AP001619.2, AP001625.4, AP001625.6, AP001626.1,AP001630.5, AP001793.1, AP003068.18, AP003774.1, AP004550.1, AP006309.4,AP1AR, AP1G1, AP1S3, AP3B1, AP3M1, AP4B1, AP5M1, APBB1IP, APBB2, APC,APCDD1L, APCDD1L-AS1, APCS, API5, API5P1, APIP, APLF, APLP2, APOA5,APOBEC2, APOBEC3B-AS1, APOBEC4, APOD, APOF, APOL1, APOL2, APOL3, APOL4,APOL6, APOO, APOOL, APPL1, AQP12A, AQP2, AQP3, AQP4, AQP9, AQR, ARAP3,ARCN1, ARF4, ARFGAP3, ARFGEF2, ARFIP1, ARG2, ARGFX, ARHGAP11A, ARHGAP12,ARHGAP24, ARHGAP27, ARHGAP31, ARHGAP31-AS1, ARHGAP42, ARHGAP44, ARHGAP5,ARHGDIB, ARHGEF12, ARHGEF15, ARHGEF26-AS1, ARHGEF3, ARHGEF37, ARHGEF38,ARHGEF6, ARID4B-IT1, ARID5A, ARID5B, ARIH1, ARIH2P1, ARL1, ARL11,ARL13A, ARL14, ARL14EP, ARE17B, ARL2BP, ARL4C, ARL4D, ARL5AP3, ARL5C,ARL6IP1, ARL6IP5, ARL8B, ARL9, ARMC1, ARMC10, ARMC10P1, ARMC2-AS1,ARMCX2, ARMCX4, ARMCX5, ARNTL, ARPC3P2, ARPC3P5, ARPC5, ARPP19, ARRDC2,ARRDC3, ARRDC5, ARSB, ARSH, ART4, ARV1, ASAH1, ASAH2, ASAH2C, ASAP1,ASB11, ASB12, ASB14, ASB18, ASB2, ASB3, ASB4, ASB5, ASB9, ASB9P1, ASCC3,ASF1A, ASNS, ASNSD1, ASPA, ASPG, ASPH, ASPN, ASS1P2, ATAD3C, ATAD5,ATF1, ATF6, ATF7, ATG10, ATG12P2, ATG16L1, ATG3, ATG4A, ATG4C, ATG5,ATL1, ATL2, ATL3, ATM, ATMIN, ATP10B, ATP10D, ATP11A-AS1, ATP11B,ATP13A3, ATP1A1, ATP1B1, ATP1B3, ATP1B4, ATP2C1, ATP5EP2, ATP5F1P6,ATP5H, ATP5HP1, ATP5JP1, ATP5L2, ATP6AP1L, ATP6AP2, ATP6V0B, ATP6V0CP1,ATP6V0CP3, ATP6V0D2, ATP6V0E1, ATP6V1A, ATP6V1C2, ATP6V1D, ATP6V1E1,ATP6V1E1P1, ATP6V1E2, ATP7A, ATP8A1, ATP8A2P3, ATP8B4, ATP8B5P, ATPBD4,ATRNL1, ATXN1, ATXN8OS, AURKAPS1, AVIL, AWAT1, AXUD1, AZGP1, AZI2,AZIN1, B2M, B3GALT5, B3GNT2, B3GNT3, B3GNT5, B3GNT7, B3GNT9,B4GALT4-AS1, B4GALT6, BAAT, BACE2, BACH1-IT1, BACH2, BAG2, BAG3, BAG4,BAG5, BAG6, BAIAP3, BANF1P1, BANK1, BARHL1, BATF2, BATF3, BBS10, BBS7,BBX, BCAN, BCAP29, BCAS2, BCCIP, BCDIN3D-AS1, BCL10, BCL2A1, BCL2L10,BCL2L13, BCL2L14, BCL2L15, BCL2L2, BCL3, BCL6, BCL6B, BCMO1, BCO2,BCORP1, BCRP8, BDNF-AS, BDP1P, BEND6, BEST3, BET1, BET3L, BHLHA15,BHLHE40, BHLHE41, BHMT2, BIN2, BIN2P1, BIRC3, BLOC1S2, BLOC1S5, BLZF1,BMI1, BMP2K, BMP5, BMP8A, BMP8B, BMPER, BMPR1APS1, BMPR1APS2, BMPR2,BMX, BNIP3L, BNIPL, BOD1L2, BOK, BOLA3, BORA, BP75, BPIFB1, BPIFB9P,BPIFC, BPIL2, BRAF, BRAFP1, BRAP, BRCA1, BRCC3, BRD2, BRD7, BRD7P2,BRD7P4, BRD7P5, BRDT, BRI3BP, BRIX1, BRMS1, BROX, BRP44L, BRWD1-IT1,BRWD1-IT2, BSN-AS2, BSND, BST2, BSX, BTAF1, BTBD16, BTC, BTF3L4P1,BTF3L4P2, BTF3P12, BTF3P7, BTG3, BTK, BTLA, BTN3A1, BTN3A3, BUB3,BX004987.3, BX004987.4, BX004987.5, BX284650.2, BX470187.1, BX571672.1,BX571672.2, BX571672.3, BX571672.5, BX649563.4, BX649597.1, BZW1,BZW1P2, C10orf10, C10orf104, C10orf108, C10orf115, C10orf118, C10orf128,C10orf129, C10orf53, C10orf62, C10orf67, C10orf85, C10orf88, C11orf1,C11orf10, C11orf20, C11orf34, C11orf52, C11orf60, C11orf63, C11orf75,C11orf85, C11orf89, C11orf91, C11orf92, C11orf93, C11orf96, C12orf23,C12orf29, C12orf4, C12orf40, C12orf5, C12orf56, C12orf60, C12orf62,C12orf66, C12orf68, C12orf69, C12orf77, C13orf15, C13orf33, C13orf35,C14orf106, C14orf142, C14orf164, C14orf182, C14orf183, C14orf28,C15orf26, C15orf29, C15orf48, C15orf52, C15orf55, C15orf56, C15orf57,C15orf59, C16orf52, C16orf70, C16orf72, C16orf88, C16orf95, C17orf104,C17orf105, C17orf51, C17orf66, C17orf80, C17orf82, C17orf99, C18orf25,C18orf34, C18orf42, C18orf54, C19orf10, C19orf2, C19orf38, C19orf67,C19orf77, C1D, C1DP1, C1DP4, C1GALT1C1, C1orf101, C1orf114, C1orf127,C1orf128, C1orf131, C1orf132, C1orf133, C1orf138, C1orf146, C1orf147,C1orf170, C1orf174, C1orf177, C1orf189, C1orf192, C1orf195, C1orf203,C1orf204, C1orf227, C1orf27, C1orf41, C1orf43, C1orf57, C1orf61,C1orf65, C1orf66, C1orf97, C1orf98, C1QA, C1QB, C1QC, C1QTNF2, C1QTNF4,C1QTNF9B, C1QTNF9B-AS1, C1S, C20orf197, C20orf26, C20orf45, C20orf72,C21orf119, C21orf128, C21orf63, C21orf7, C21orf77, C21orf91,C21orf91-OT1, C22orf24, C22orf25, C22orf26, C22orf28, C22orf34, C2CD4A,C2CD4B, C2orf18, C2orf27A, C2orf30, C2orf32, C2orf42, C2orf44, C2orf47,C2orf50, C2orf61, C2orf65, C2orf69, C2orf70, C2orf71, C2orf73, C2orf76,C3AR1, C3orf14, C3orf15, C3orf26, C3orf33, C3orf38, C3orf70, C4BPAP1,C4BPB, C4orf22, C4orf27, C4orf32, C4orf33, C4orf34, C4orf45, C4orf47,C4orf51, C4orf52, C5AR1, C5orf17, C5orf22, C5orf27, C5orf28, C5orf30,C5orf32, C5orf34, C5orf43, C5orf50, C5orf51, C5orf53, C5orf54, C5orf58,C5orf60, C5orf63, C6orf115, C6orf117, C6orf130, C6orf132, C6orf160,C6orf203, C6orf222, C6orf225, C6orf62, C6orf89, C7orf10, C7orf23,C7orf25, C7orf30, C7orf31, C7orf42, C7orf52, C7orf57, C7orf63, C8orf4,C8orf40, C8orf46, C8orf47, C8orf74, C9orf106, C9orf119, C9orf135,C9orf139, C9orf152, C9orf153, C9orf24, C9orf3, C9orf40, C9orf41,C9orf72, C9orf9, C9orf91, C9orf95, CA1, CA12, CA13, CA5A, CA5B,CA5B-AS1, CA7, CA8, CAB39, CAB39L, CABLES1, CABP1, CABP4, CABP5, CABP7,CACNA1C-AS3, CACNA1D, CACNA2D4, CACYBP, CADM1, CALM1, CALM2P4, CALU,CAMK2D, CAMKK1, CAMLG, CAMTA1-IT1, CANX, CAP2P1, CAPN11, CAPN13, CAPN7,CAPN8, CAPZA3, CARD16, CARD6, CASC4, CASC4P1, CASP1, CASP10, CASP3P1,CASP4, CASP8, CASP8AP2, CASQ1, CASQ2, CASR, CASS4, CAST, CATSPER4,CATSPERB, CATSPERD, CBX1P4, CBX3P1, CBX7, CC2D2B, CCDC104, CCDC109B,CCDC110, CCDC117, CCDC121, CCDC125, CCDC144A, CCDC144B, CCDC144C,CCDC147, CCDC15, CCDC155, CCDC158, CCDC163P, CCDC28A, CCDC36, CCDC47,CCDC48, CCDC53, CCDC58P1, CCDC59, CCDC6, CCDC66, CCDC67, CCDC7, CCDC70,CCDC73, CCDC75, CCDC81, CCDC84, CCDC86, CCDC87, CCDC89, CCDC90A, CCDC91,CCL11, CCL18, CCL2, CCL22, CCL24, CCL28, CCL3, CCL3L1, CCL4, CCNA2,CCNC, CCND1, CCND2, CCND3, CCNG1, CCNH, CCNI, CCNO, CCNT1, CCNYL2,CCNYL3, CCP110, CCPG1, CCR1, CCR3, CCR5, CCR7, CCRL1, CCRL2, CCRN4L,CCSAP, CCT4, CCT4P2, CCT5P2, CCT6P2, CCT6P4, CCT7P1, CCT8, CCT8L1P,CCT8P1, CD14, CD163, CD163L1, CD180, CD1D, CD200R1, CD209, CD22, CD244,CD274, CD2AP, CD300E, CD300LB, CD300LF, CD300LG, CD302, CD33, CD38,CD40, CD44, CD46, CD48, CD5, CD53, CD55, CD58, CD59, CD68, CD72, CD79B,CD80, CD83, CD84, CD86, CD9, CD93, CD99, CDADC1, CDC14A, CDC14B, CDC26,CDC27P1, CDC37L1, CDC42BPA, CDC42EP5, CDC5L, CDC6, CDC7, CDC73, CDCA2,CDH19, CDH22, CDH26, CDH5, CDHR4, CDK14, CDK2AP2P1, CDK2AP2P2, CDK6,CDK7, CDK8, CDKL3, CDKL4, CDKN1A, CDKN1B, CDKN2A, CDKN2AIPNLP1, CDKN2B,CDKN2B-AS1, CDKN2C, CDNF, CDR2, CDRT1, CDV3, CEACAM21, CEACAM3, CEACAM6,CEACAM7, CEACAMP5, CEBPB, CEBPD, CEBPE, CEBPG, CEBPZ, CECR7, CEL,CELA2A, CELA2B, CELA3A, CELA3B, CELP, CENPC1, CENPC1P1, CENPQ, CENPW,CEP120, CEP128, CEP152, CEP350, CEP41, CEP44, CEP57L1, CEP57L1P1, CEP63,CEP70, CEP76, CEPT1, CERK, CERS3, CERS6, CES1P1, CETN3, CETN4P, CETP,CFC1B, CFH, CFI, CFL1P4, CFL1P5, CFL2, CFLAR, CFLAR-AS1, CFTR, CGB7,CGGBP1, CGI-148P, CGRRF1, CHAC2, CHAF1B, CHAMP1, CHCHD10, CHCHD2,CHCHD2P2, CHCHD2P6, CHCHD4, CHCHD7, CHCHD9, CHD1, CHD1L, CHD9, CHEK2P2,CHGB, CHI3L2, CHIT1, CHL1-AS1, CHM, CHMP1B, CHMP2B, CHMP4BP1, CHMP5,CHN1, CHODL, CHORDC1, CHPF, CHPT1, CHRDL2, CHRM1, CHRM4, CHRNA1, CHRNA3,CHRNA5, CHRNA9, CHRNG, CHST1, CHST2, CHUK, CHURC1, CIB1, CICP3, CICP5,CICP6, CICP9, CIDEA, CIR1P1, CIR1P2, CISD1, CISH, CITED2, CKAP4, CKLF,CLCA1, CLCA2, CLCA3P, CLCA4, CLCC1, CLCN3, CLCN4, CLDN12, CLDN14, CLDN2,CLDN4, CLDN5, CLDN9, CLEC10A, CLEC14A, CLEC17A, CLEC18A, CLEC18C,CLEC1A, CLEC3A, CLEC4D, CLEC4G, CLEC4M, CLEC5A, CLEC7A, CLGN, CLINT1,CLIP1, CLIP4, CLK1, CLK4, CLLU1OS, CLMN, CLN5, CLOCK, CLRN2, CLTC,CLVS1, CMA1, CMAHP, CMBL, CMC1, CMKLR1, CMPK1, CNBP, CNOT10-AS1, CNOT6L,CNOT6LP1, CNOT7, CNOT7P1, CNOT8, CNP, CNR2, CNRIP1, CNST, CNTD1, CNTN1,CNTN4, CNTN4-AS2, CNTN5, COA5, COG3, COG5, COG6, COL10A1, COL13A1,COL15A1, COL20A1, COL24A1, COL28A1, COL4A3, COL5A3, COLEC10, COLEC12,COMMD3, COMMD6, COMP, COPB1, COPB2, COPS2, COPS4, COPZ1, COPZ2, COQ10B,COQ3, CORO6, CORO7, CORT, COX11P1, COX17, COX17P1, COX20, COX5AP2,COX5BP2, COX6A2, COX6B1P1, COX6CP1, COX7A1, COX7A2P1, COX7B, COX7CP1,CP, CPA1, CPA4, CPB1, CPD, CPE, CPEB3, CPEB4, CPLX4, CPNE3, CPNE4,CPNE8, CPO, CPQ, CPSF2, CPSF4L, CPT1A, CPT2, CR2, CR381653.2, CREB3L2,CREB5, CREBL2, CREBRF, CREG1, CREM, CRIP1, CRNKL1, CRP, CRTAP, CRY1,CRYAB, CRYBG3, CRYZ, CSDE1, CSE1L, CSF2, CSF2RB, CSGALNACT2, CSNK1A1P3,CSNK2A1P, CSRNP1, CST2, CST7, CTA-126B4.7, CTA-14H9.5, CTA-204B4.6,CTA-211A9.5, CTA-212D2.2, CTA-215D11.4, CTA- 229A8.5, CTA-246H3.11,CTA-253N17.1, CTA-276O3.4, CTA-292E10.7, CTA- 299D3.8, CTA-313A17.2,CTA-360L10.1, CTA-363E6.6, CTA-440B3.1, CTA- 833B7.2, CTA-972D3.2,CTAGE1, CTAGE10P, CTAGE11P, CTAGE13P, CTAGE3P, CTAGE5, CTAGE6P, CTAGE9,CTB-102L5.4, CTB-104F4.2, CTB- 109A12.1, CTB-113P19.3, CTB-118N6.1,CTB-118N6.2, CTB-118N6.3, CTB- 120L21.1, CTB-12O2.1, CTB-131B5.4,CTB-131B5.5, CTB-131K11.1, CTB- 133G6.1, CTB-134H23.3, CTB-13H5.1,CTB-140J7.2, CTB-157D17.1, CTB- 158E9.2, CTB-161M19.1, CTB-161M19.4,CTB-193M12.1, CTB-31C7.1, CTB- 31N19.2, CTB-35F21.1, CTB-35F21.2,CTB-35F21.4, CTB-36O1.3, CTB-3M24.3, CTB-43P18.1, CTB-46B19.1,CTB-49A3.5, CTB-50L17.16, CTB-50L17.7, CTB- 51J22.1, CTB-54D4.1,CTB-55O6.10, CTB-55O6.4, CTB-75G16.1, CTBS, CTC- 209H22.3, CTC-228N24.1,CTC-228N24.3, CTC-250I14.1, CTC-251H24.1, CTC- 260E6.6, CTC-260F20.5,CTC-263F14.5, CTC-264K15.6, CTC-265F19.1, CTC- 265F19.2, CTC-281B15.1,CTC-297N7.10, CTC-303L1.1, CTC-308K20.1, CTC- 308K20.2, CTC-308K20.3,CTC-329H14.1, CTC-338M12.1, CTC-338M12.5, CTC- 339F2.2, CTC-347C20.1,CTC-422A18.1, CTC-428G20.1, CTC-431G16.2, CTC- 439O9.2, CTC-444D3.7,CTC-448D22.1, CTC-454I21.3, CTC-454M9.1, CTC- 457E21.1, CTC-457L16.2,CTC-459F4.1, CTC-459F4.3, CTC-459F4.6, CTC- 459F4.7, CTC-463N11.1,CTC-471C19.1, CTC-471J1.1, CTC-471J1.2, CTC- 493L21.1, CTC-498J12.3,CTC-499B15.4, CTC-499B15.7, CTC-499B15.8, CTC- 504A5.1, CTC-506B8.1,CTC-512J14.7, CTC-523E23.4, CTC-524C5.5, CTC- 534A2.2, CTC-534B23.1,CTC-542B22.2, CTC-543D15.3, CTC-548K16.6, CTC- 550B14.7, CTC-551A13.2,CTC-559E9.2, CTC-559E9.4, CTC-756D1.3, CTC- 774J1.2, CTC-782O7.2,CTC-788C1.1, CTD-2003C8.1, CTD-2005H7.1, CTD- 2005H7.2, CTD-2006C1.10,CTD-2006C1.12, CTD-2006C1.13, CTD-2006K23.1, CTD-2007H13.1,CTD-2007H13.3, CTD-2008P7.1, CTD-2008P7.10, CTD- 2008P7.3, CTD-2008P7.9,CTD-2012K14.7, CTD-2013N17.1, CTD-2013N24.2, CTD-2014B16.3,CTD-2015B23.2, CTD-2017C7.1, CTD-2022H16.3, CTD- 2024I7.13,CTD-2024P10.1, CTD-2026G6.1, CTD-2026G6.2, CTD-2026K11.2, CTD-2026K11.3,CTD-2031P19.4, CTD-2031P19.5, CTD-2034I21.2, CTD- 2036P10.3,CTD-2047H16.2, CTD-2050B12.1, CTD-2050N2.1, CTD-2058B24.3,CTD-2060C23.1, CTD-2061E19.1, CTD-2072I24.1, CTD-2085F10.1, CTD-2085J24.3, CTD-2086L14.1, CTD-2086O20.3, CTD-2089O24.1, CTD-2095E4.1,CTD-2104P17.1, CTD-2105E13.13, CTD-2116N17.1, CTD-2119F7.2, CTD-2122P11.1, CTD-2130O13.2, CTD-2134P3.1, CTD-2138O14.1, CTD-2139B15.2,CTD-2140G10.2, CTD-2144E22.10, CTD-2145A24.3, CTD-2154I11.1, CTD-2154I11.2, CTD-2162K18.3, CTD-2162K18.5, CTD-2165H16.3, CTD-2165H16.4,CTD-2175M1.1, CTD-2179L22.1, CTD-2184C24.2, CTD-2184D3.4, CTD- 2184D3.5,CTD-2189E23.2, CTD-2193P3.2, CTD-2195M18.1, CTD-2198K18.1, CTD-2201E9.1,CTD-2201E9.2, CTD-2206G10.2, CTD-2207P18.1, CTD- 2210P15.2,CTD-2210P24.4, CTD-2213F21.2, CTD-2215E18.1, CTD-2215L10.1,CTD-2224J9.3, CTD-2224J9.8, CTD-2228K2.1, CTD-2228K2.2, CTD-2240E14.4,CTD-2240H23.2, CTD-2240J17.1, CTD-2245E15.3, CTD-2246P4.1, CTD-2248H3.1, CTD-2256P15.1, CTD-2265D6.1, CTD-2265O21.3, CTD-2267D19.2,CTD-2270L9.2, CTD-2272G21.2, CTD-2277K2.1, CTD-2281D19.1, CTD-2281M20.1, CTD-2286N8.2, CTD-2287O16.1, CTD-2288F12.1, CTD-2288O8.1,CTD-2292M16.8, CTD-2292P10.2, CTD-2292P10.4, CTD-2293H3.2, CTD-2302E22.3, CTD-2302E22.4, CTD-2307P3.1, CTD-2308G16.1, CTD-2313J17.1,CTD-2313J17.2, CTD-2313J17.5, CTD-2313N18.2, CTD-2314B22.3, CTD-2319I12.1, CTD-2319I12.3, CTD-2319I12.4, CTD-2319I12.5, CTD-2323K18.1,CTD-2323K18.3, CTD-2324F15.2, CTD-2329K10.1, CTD-2331D11.1, CTD-2335A18.1, CTD-2337A12.1, CTD-2345M20.1, CTD-2349P21.1, CTD-2349P21.11,CTD-2349P21.9, CTD-2366F13.1, CTD-2369P2.8, CTD-2373H9.5, CTD-2373H9.6,CTD-2380F24.1, CTD-2382E5.1, CTD-2382E5.4, CTD-2501E16.1, CTD-2503H21.2, CTD-2503O16.2, CTD-2509G16.4, CTD-2509G16.5, CTD-2510F5.4,CTD-2514C3.1, CTD-2515C13.1, CTD-2516F10.4, CTD-2516K3.3, CTD-2517M22.9, CTD-2521M24.4, CTD-2522E6.4, CTD-2526A2.2, CTD-2526L21.3,CTD-2526M8.2, CTD-2528L19.3, CTD-2529O21.1, CTD-2531D15.4, CTD-2537I9.13, CTD-2537I9.5, CTD-2537O9.1, CTD-2538C1.3, CTD-2540L5.3, CTD-2540L5.6, CTD-2540M10.1, CTD-2541M15.1, CTD-2544N14.3, CTD-2545H1.1,CTD-2553C6.1, CTD-2555C10.3, CTD-2555K7.1, CTD-2555O16.2, CTD-2561B21.11, CTD-2574D22.4, CTD-2574D22.5, CTD-2574D22.6, CTD-2583P5.3,CTD-2589O24.1, CTD-2595P9.1, CTD-2609K8.3, CTD-2630F21.1, CTD-2631K10.1, CTD-2644I21.1, CTD-2647E9.1, CTD-2650P22.1, CTD-2653M23.1,CTD-3010D24.3, CTD-3035D6.1, CTD-3035D6.2, CTD-3049M7.1, CTD- 3051D23.4,CTD-3057O21.1, CTD-3064C13.1, CTD-3064H18.6, CTD-3064M3.4, CTD-3064M3.6,CTD-3065B20.2, CTD-3083F21.1, CTD-3083F21.5, CTD- 3092A11.1,CTD-3105H18.11, CTD-3105H18.13, CTD-3110H11.1, CTD- 3118D11.2,CTD-3157E16.1, CTD-3162L10.1, CTD-3162L10.3, CTD-3162L10.5,CTD-3185P2.1, CTD-3193O13.1, CTD-3220F14.2, CTD-3234P18.2, CTD-3239E11.2, CTD-3244O18.6, CTD-3247F14.2, CTDSPL2, CTF2P, CTGLF12P,CTNNA3, CTNNAP1, CTR9, CTRB1, CTRB2, CTRC, CTSF, CTSL1, CTSL2, CTSO,CTSS, CTSW, CUL3, CUL4B, CUL5, CUTC, CUZD1, CWC15, CWC22, CWC27,CWF19L1, CWF19L2, CX3CR1, CXCL10, CXCL16, CXCL17, CXCL3, CXCR3, CXCR6,CXorf21, CXorf22, CXorf24, CXorf26, CXorf36, CXorf57, CXorf67, CYB5R1,CYB5R4, CYBRD1, CYCS, CYCSP55, CYLD, CYP17A1, CYP17A1-AS1, CYP19A1,CYP1A1, CYP1B1, CYP2A6, CYP2A7, CYP2C18, CYP2G1P, CYP2J2, CYP2U1,CYP3A43, CYP3A5, CYP3A7, CYP4F11, CYP4F12, CYP4F24P, CYP4F25P, CYP4F3,CYP4F43P, CYP4V2, CYP51P2, CYS1, CYSLTR1, CYSTM1, CYTIP, CYYR1, DAAM1,DACH2, DAD1, DAP, DAP3P1, DAPK1-IT1, DAPK2, DAPL1, DAPP1, DARS, DARS2,DAXX, DAZAP2, DAZAP2P1, DAZL, DBIL5P, DBNDD2, DBR1, DCAF10, DCAF13P3,DCAF17, DCAF4L1, DCBLD1, DCDC1, DCDC2, DCLK3, DCLRE1A, DCT, DCTN4,DCTN6, DCUN1D4, DDHD1, DDHD2, DDI2, DDO, DDX1, DDX10, DDX11-AS1,DDX11L10, DDX11L2, DDX11L5, DDX18, DDX21, DDX24, DDX26B, DDX3Y, DDX3YP2,DDX4, DDX43, DDX46, DDX50, DDX50P2, DDX55, DDX60, DDX60L, DDX6P2, DEFB1,DEFB109P1, DEFB109P1B, DEFB135, DEGS1, DEK, DENND2D, DENND4A, DEPTOR,DERL1, DERL2, DERL3, DES, DESI2, DGCR11, DGCR5, DGCR6, DGKB, DGKD, DGKE,DHFRL1, DHRS7, DHRS7B, DHRS9, DHX29, DHX32, DHX40, DHX58, DHX9P1,DIAPH1, DIEXF, DIO1, DIO2, DIP2C, DIS3, DIXDC1, DKFZp686O24166, DKK4,DLAT, DLEU1, DLEU2, DLEU2L, DLG1, DLG1-AS1, DLG2, DLG3-AS1, DLGAP1-AS1,DLGAP1-AS2, DLX6, DMC1, DMGDH, DMP1, DMRTA1, DMRTA2, DMXL1, DNA2, DNAH3,DNAH5, DNAH6, DNAJA1P3, DNAJA4, DNAJB1, DNAJB11, DNAJB14, DNAJB3,DNAJB4, DNAJB8-AS1, DNAJB9, DNAJC12, DNAJC14, DNAJC15, DNAJC22, DNAJC25,DNAJC25-GNG10, DNAJC3, DNAJC3-AS1, DNAJC5B, DNASE2B, DNM1, DNM1P32,DNM3, DNM3-IT1, DNMT3L, DNTT, DNTTIP2, DOCK10, DOCK11, DOCK3, DOCK9,DOK2, DOK7, DOM3Z, DPEP2, DPH3P1, DPM1, DPM2, DPM3, DPPA3P1, DPRX,DPRXP4, DPT, DPY19L2P4, DPYS, DR1, DRAM1, DRAM2, DRD5P1, DSCR4-IT1,DSCR8, DSTN, DSTNP1, DSTNP2, DSTYK, DTWD1, DTWD2, DTX2,DTX2P1-UPK3BP1-PMS2P11, DTX3L, DUOX2, DUOXA2, DUS4L, DUSP11, DUSP19,DUSP2, DUSP23, DUSP26, DUSP5, DUSP5P, DUTP7, DYDC1, DYDC2, DYM, DYNC1I1,DYNC2H1, DYNC2LI1, DYNLL2, DYNLT3, DYNLT3P1, DYNLT3P2, DYRK1A, DYRK3,DYRK4, DYTN, DZIP1, EAF1, FAF1-AS1, EAF2, EAPP, EBAG9, EBI3, ECEL1P2,ECI2, ECM1, EDA2R, EDEM1, EDEM3, EDIL3, EDN3, EDNRB, EEA1, EED,EEF1A1P24, EEF1A1P29, EEF1A1P30, EEF1A1P33, EEF1A1P41, EEF1B2, EEF1B2P2,EEF1B2P3, EEF1DP3, EEF1DP5, EEF1G, EEPD1, EFCAB10, EFCAB13, EFCAB6-AS1,EFHA1, EFHC2, EFHD1, EFNA5, EFR3A, EFTUD1P1, EGF, EGFLAM, EGLN1, EGOT,EGR3, EHBP1, EHBP1L1, EHF, EHHADH, EHHADH-AS1, EI24, EID3, EIF1, EIF1AY,EIF2A, EIF2AK1, EIF2AK2, EIF2AK3, EIF2B3, EIF2C2, EIF2S1, EIF2S2P3,EIF2S2P4, EIF2S3L, EIF3A, EIF3E, EIF3H, EIF3J, EIF3M, EIF4A2, EIF4B,EIF4BP3, EIF4BP5, EIF4BP6, EIF4BP7, EIF4E, EIF4E1B, EIF4E3, EIF5A2,EIF5AL1, EIF5AP2, EIF5AP3, EIF5B, ELA3A, ELAVL4, ELK2BP, ELK4, ELL2P1,ELL3, ELMO1, ELMO3, ELOVL3, ELOVL5, ELOVL7, ELP2, ELP4, ELTD1, EMB,EMBP1, EMC2, EMC3, EMC7, EME1, EMG1, EML5, EMP1, EMP2, EMP3, EMR1, EMR2,EMR3, EMX1, EN1, ENAM, ENDOD1, ENDOU, ENKUR, ENO1-IT1, ENOSF1,ENOX1-AS1, ENOX2, ENPP2, ENPP3, ENPP4, ENPP5, ENTPD3, ENTPD3-AS1, EPAS1,EPB41L2, EPB41L4B, EPCAM, EPDR1, EPHA1-AS1, EPHA2, EPHA5, EPM2AIP1,EPRS, EPS15, ERAP2, ERAS, ERCC4, ERCC5, ERCC6, ERCC6L2, ERCC8, EREG,ERG, ERGIC2, ERHP1, ERI1, ERLEC1, ERLIN1, ERLIN2, ERMN, ERMP1, ERO1LB,ERP27, ERP29P1, ERP44, ERRFI1, ERV3-1, ERVFRD-1, ERVH48-1, ESCO2, ESF1,ESM1, ESR1, ESR2, ESRG, ESRP1, ETF1, ETF1P2, ETFDH, ETNK1, ETS1, ETS2,ETV5, ETV5-AS1, ETV7, EVI2B, EVI5, EXD1, EXOC1, EXOC5, EXOC8, EXOSC3P1,EXOSC9, EXPH5, F11, F2RL3, F8, F8A1, FABP1, FABP4, FABP5P3, FAF1, FAIM3,FAM102A, FAM103A2P, FAM104A, FAM105A, FAM106A, FAM107A, FAM108A7P,FAM108C1, FAM109B, FAM110C, FAM114A1, FAM115C, FAM115D, FAM117A,FAM120A, FAM122B, FAM129A, FAM132B, FAM133A, FAM133B, FAM133CP,FAM133DP, FAM134B, FAM135A, FAM138D, FAM13A, FAM13C, FAM149A,FAM149B1P1, FAM150B, FAM151B, FAM153A, FAM153B, FAM153C, FAM155A-IT1,FAM156A, FAM159B, FAM160A1, FAM160B1, FAM167A, FAM169A, FAM169B,FAM175A, FAM175B, FAM176C, FAM177A1, FAM177B, FAM179B, FAM180A, FAM182A,FAM182B, FAM183B, FAM186A, FAM18B, FAM18B1, FAM18B2-CDRT4, FAM190A,FAM190B, FAM199X, FAM19A3, FAM19A4, FAM200A, FAM205A, FAM206A, FAM208B,FAM209A, FAM209B, FAM216A, FAM217A, FAM220A, FAM227B, FAM23B, FAM24B,FAM25G, FAM26E, FAM26F, FAM27A, FAM27B, FAM27C, FAM27D1, FAM27E1,FAM27E3, FAM35A, FAM35B2, FAM3B, FAM3C, FAM3C2, FAM40B, FAM45B, FAM46C,FAM47C, FAM47E, FAM50B, FAM53A, FAM58A, FAM59A, FAM60A, FAM63B, FAM66A,FAM70A, FAM71A, FAM71E2, FAM71F1, FAM72A, FAM72C, FAM72D, FAM75C1,FAM82A1, FAM83C, FAM83C-AS1, FAM86DP, FAM87B, FAM8A1, FAM90A25P,FAM90A2P, FAM92A1P1, FAM95B1, FAM98A, FAM9C, FANCB, FANCF, FANCL, FAP,FAR1, FAR2, FARSB, FAS, FASTKD1, FASTKD2, FAT1, FBXL17, FBXL3, FBXL5,FBXL8, FBXO22, FBXO25, FBXO28, FBXO30, FBXO32, FBXO33, FBXO34, FBXO39,FBXO4, FBXO43, FBXO45, FBXO47, FBXO48, FBXO7, FBXO8, FBXW10, FBXW11P1,FBXW7, FCAMR, FCER1G, FCGBP, FCGR2A, FCGR2C, FCGR3A, FCHO2, FCN3, FCRL6,FDPSP1, FDPSP4, FDPSP5, FEM1B, FFAR3, FGD2, FGF14-IT1, FGF19, FGF20,FGF6, FGF7, FGFBP1, FGFR1OP2, FGL2, FGR, FHDC1, FHL5, FICD, FIG.F,FIG.NL1, FITM2, FKBP11, FKBP14, FKBP4P1, FKBP5, FKTN, FLG, FLG2,FLG-AS1, FLI1, FLJ14712, FLJ37644, FLJ41603, FLJ43752, FLT1, FLT3,FLT3LG, FLT4, FLVCR2, FMN1, FMN2, FMO2, FMO5, FMOD, FNDC3A, FNDC3B,FNDC5, FNDC9, FNIP1, FNIP2, FNTAL1, FNTAP2, FOLR2, FOSL1, FOSL1P1,FOSL2, FOXC2, FOXD2-AS1, FOXE1, FOXF1, FOXF2, FOXJ2, FOXJ3, FOXL1,FOXN2, FOXN4, FOXO1, FOXO3, FOXQ1, FOXS1, FPGT, FPGT-TNNI3K, FPR1, FPR3,FREM3, FRG1, FRG1B, FRK, FRMD7, FRRS1, FRS2, FSBP, FSD2, FSHR, FTH1P10,FTH1P11, FTH1P2, FTH1P23, FTH1P3, FTH1P4, FTLP14, FTO-IT1, FUCA1, FUCA2,FUNDC2, FUNDC2P2, FUT3, FUT5, FUT7, FVT1, FXC1, FXR1, FXYD2, FXYD5,FXYD6P2, FYB, FYCO1, FYTTD1, FYTTD1P1, FZD4, FZD9, G3BP1, G3BP2, G6PC2,GAB3, GABARAPL1, GABARAPL3, GABRA1, GABRA2, GABRR1, GABRR2, GAD1, GAD2,GADD45A, GADD45B, GADD45G, GAL3ST2, GALK2, GALNT10, GALNT14, GALNT3,GALNT7, GALNT8, GALNTL2, GALNTL5, GAN, GAPDHP14, GAPDHP2, GAPDHP20,GAPDHP23, GAPDHP33, GAPDHP40, GAPDHP47, GAPDHP49, GAPDHP55, GAPDHP58,GAPDHP60, GAPDHP61, GAPDHP63, GAPDHP69, GAPDHP71, GAPDHP72, GAR1, GARS,GAS2, GAS5, GBA3, GBAS, GBE1, GBP1, GBP1P1, GBP2, GBP4, GBP5, GCC1,GCFC2, GCGR, GCLM, GCM1, GCNT1P1, GCNT3, GCNT4, GCNT7, GCOM1, GCOM2,GCSAML, GDA, GDAP2, GDI2, GDI2P1, GDI2P2, GDNF, GDPGP1, GEM, GEMIN2,GEMIN8P3, GFI1B, GFM1, GFPT1, GFPT2, GGCT, GGNBP1, GGT5, GGT6, GH1, GH2,GHc-362H12.3, GHDC, GHITM, GHRHR, GHRLOS2, GHSR, GIMAP4, GIMAP5, GIMAP6,GIMAP8, GIN1, GINS3, GJA5, GJA8, GJB3, GJD2, GK3P, GKAP1, GK-AS1,GK-IT1, GLB1L3, GLCE, GLE1, GLI1, GLIPR1, GLIPR1L2, GLIS3, GLO1, GLP1R,GLRA1, GLRA3, GLRB, GLRX2, GLRX3, GLRXP3, GLT25D2, GLT8D1, GLT8D2, GLTP,GLTPP1, GMCL1, GMCL1P1, GMFB, GMNN, GMPR, GMPS, GNA13, GNA15, GNAS,GNAS-AS1, GNB4, GNE, GNG11, GNG12, GNG2, GNG4, GNGT1, GNGT2, GNL2, GNL3,GNL3LP1, GNLY, GNPDA1, GNPDA2, GNRHR, GNS, GOLGA2, GOLGA2P4, GOLGA4,GOLGA5, GOLGA6A, GOLGA7B, GOLGA8C, GOLGA8E, GOLGA8H, GOLGB1, GOLPH3L,GOLSYN, GOLT1A, GOLT1B, GOPC, GORASP2, GOSR2, GOT1, GOT2P2, GP1BA, GP2,GP5, GP6, GPAM, GPBP1, GPD1, GPD1L, GPD2, GPHN, GPM6A, GPN3, GPNMB,GPR110, GPR115, GPR116, GPR144, GPR150, GPR158, GPR158-AS1, GPR17,GPR177, GPR183, GPR19, GPR27, GPR3, GPR31, GPR34, GPR37L1, GPR4, GPR52,GPR56, GPR6, GPR61, GPR65, GPR75, GPR84, GPR87, GPR88, GPR89A, GPR97,GPRASP1, GPRC5D, GPRC6A, GPSM2, GPX1P2, GPX2, GPX3, GRAMD1B, GRAMD1C,GRAMD3, GRAP, GRAPL, GREM1, GREM2, GRHL3, GRIA2, GRIA4, GRIK1-AS1,GRIN2A, GRIP2, GRK7, GRM4, GRM7-AS3, GRP, GRPEL2, GRPEL2P2, GS1-174L6.4,GS1-179L18.1, GS1- 184P14.2, GS1-211B7.1, GS1-251I9.2, GS1-251I9.3,GS1-251I9.4, GS1-304P7.1, GS1-309P15.4, GS1-44D20.1, GS1-465N13.1,GS1-542M4.3, GS1-600G8.5, GSDMA, GSN, GSN-AS1, GSPT1, GSTA2, GSTO1,GSTP1P1, GTDC1, GTF2A1, GTF2A2, GTF2B, GTF2E2, GTF2F2, GTF2H2C, GTF2H5,GTF2IRD1P1, GTF3C3, GTPBP10, GUCA2A, GUCY1A3, GUCY1B3, GUCY2C, GUK1,GUSBP2, GUSBP4, GUSBP9, GVINP1, GXYLT1, GXYLT2, GYG1, GYG1P1, GYG1P3,GYLTL1B, GYPB, GYPE, GYS2, GZMB, GZMM, H2AFB1, H2AFZ, H2AFZP3, H2AFZP6,H3F3AP5, H3F3BP1, HABP4, HADH, HADHAP1, HAPLN1, HAPLN4, HAR1A, HAR1B,HAS1, HAT1, HAUS1P3, HAUS3, HAUS4, HAUS6, HAUS6P1, HAUS7, HAVCR2, HBEGF,HBS1L, HBXIP, HCFC1-AS1, HCFC2, HCFC2P1, HCG4P3, HCG4P5, HCK, HCLS1,HCRT, HCST, HDAC11-AS1, HDAC9, HDDC3, HDGFP1, HDHD1P1, HEATR1, HEATR4,HEBP2, HECA, HECTD1, HELQ, HERC2P4, HERC2P5, HERC3, HERC4, HERC5, HERC6,HERPUD1, HESX1, HEXA-AS1, HEXB, HEY1, HFE, HGD, HGF, HHAT, HHATL,HHATL-AS1, HHIPL2, HHLA2, HIAT1, HIATL1, HIATL2, HIBADH, HIBCH, HIF1A,HIGD1AP10, HIGD1AP11, HIGD1AP16, HILPDA, HIN1L, HINT1P1, HIPK1, HIPK3,HIST1H1A, HIST1H1T, HIST1H2AI, HIST1H2AK, HIST1H2BE, HIST1H2BI,HIST1H2BN, HIST1H3H, HIST1H4A, HIST1H4B, HIST1H4PS1, HIST2H2BA,HIST2H2BB, HIST2H4B, HIVEP2, HLA-A, HLA-A29.1, HLA-B, HLA-C, HLA-F,HLA-F-AS1, HLA-H, HLF, HLTF, HLX, HLXB9, HM13-IT1, HMGB1, HMGB1P14,HMGB1P27, HMGB1P3, HMGB1P31, HMGB1P44, HMGB1P9, HMGB2, HMGB2P1, HMGB3P1,HMGB3P17, HMGB3P5, HMGB3P6, HMGB3P7, HMGN1P24, HMGN1P30, HMGN1P7,HMGN1P8, HMGN2P28, HMGN2P41, HMGN2P6, HMGN2P8, HMGN4, HMGN5, HMGXB4,HMOX1, HNRNPA1P14, HNRNPA1P15, HNRNPA1P26, HNRNPA1P28, HNRNPA1P3,HNRNPA1P4, HNRNPA1P6, HNRNPA1P7, HNRNPA3P1, HNRNPA3P2, HNRNPC, HNRNPCL1,HNRNPH2, HNRNPKP1, HNRNPKP2, HNRNPKP5, HNRNPU-AS1, HNRPCP, HOMER2,HOMEZ, HOOK1, HOPX, HORMAD2, HOXA7, HOXB4, HOXB5, HOXB6, HP, HPCAL4,HPGD, HPRT1, HPS5, HR, HRASLS3, HRG, HRH1, HRNR, HS3ST2, HS6ST2,hsa-mir-142, hsa-mir-146a, hsa- mir-1539, hsa-mir-2117, hsa-mir-3149,hsa-mir-3180-4, hsa-mir-4763, hsa-mir-6080, hsa-mir-6723, HSBP1L1,HSD11B1, HSD17B12, HSD17B13, HSD17B4, HSD17B6, HSD17B7P2, HSD17B8,HSD3BP2, HSD3BP5, HSDL2, HSF4, HSF5, HSFX1, HSH2D, HSP90AA1, HSP90AA5P,HSP90AA6P, HSP90AB2P, HSP90AB3P, HSP90AB6P, HSP90B1, HSP90B2P, HSP90B3P,HSPA13, HSPA1A, HSPA1B, HSPA2, HSPA4L, HSPA5, HSPA6, HSPA7, HSPA9,HSPA9P1, HSPB1P1, HSPB3, HSPB6, HSPB9, HSPD1, HSPD1P1, HSPD1P10,HSPD1P11, HSPD1P3, HSPD1P5, HSPD1P6, HSPE1, HSPH1, HTATIP2, HTR1D,HTR1F, HTR2B, HTR3D, HTR3E, HTR6, HTR7, HTRA3, HTRA4, HTT-AS1, HULC,HUS1B, HYAL4, IAH1, IAPP, IARS, IARS2, IBSP, IBTK, ICAM1, ICAM2, ICAM4,ICAM5, ICK, ICOSLG, ID2B, IDE, IDNK, IDO1, IDS, IDSP1, IER3, IER3IP1,IER5, IFI16, IFI30, IFI35, IFI44, IFI44L, IFIH1, IFIT1, IFIT2, IFIT3,IFIT5, IFLTD1, IFNA5, IFNAR2, IFNGR1, IFNW1, IFT20, IFT74, IFT88,IGBP1-AS2, IGBP1P1, IGBP1P4, IGF1R, IGF2-AS, IGFBP4, IGFBP7, IGFL2,IGIP, IGKV1-16, IGKV1-17, IGKV1D-17, IGLL3P, IGLV5-52, IGLV9-49,IGLVIV-59, IGSF11, IGSF11-AS1, IGSF5, IKBKAP-IT1, IKBKGP1, IKZF2, IKZF5,IL10, IL10RB, IL11, IL12RB1, IL12RB2, IL13RA1, IL13RA2, IL17B, IL17RB,IL17RE, IL18RAP, IL19, IL1A, IL1B, IL1R1, IL1R2, IL1RL1, IL1RL2, IL1RN,IL20, IL20RA, IL20RB, IL21R, IL21R-AS1, IL22RA1, IL23A, IL24, IL29,IL2RA, IL2RB, IL2RG, IL31, IL33, IL36A, IL36G, IL5, IL5RA, IL6, IL6R,IL6ST, IL7R, IL8, ILDR1, ILF3-AS1, IMMP1L, IMMP2L, IMMTP1, IMPA1P,IMPAD1, IMPDH1P11, IMPDH1P6, IMPG1, IMPG2, ING2, INGX, INHBA, INHBA-AS1,INHBC, INPP4B, INS, INSC, INSIG1, INS-IGF2, INSL3, INSL5, INSM2, INSRR,INTS4L2, INTS6, INTS6-AS1, INTS6P1, IPCEF1, IPMK, IPO7, IPO7P1, IPO7P2,IPO8, IPO8P1, IQCB1, IQCB2P, IQCF3, IQCH, IQCH-AS1, IQGAP1, IQUB, IRAK2,IRAK4, IRF1, IRF4, IRF5, IRF8, IRS2, ISCA1, ISCA1P1, ISCA1P4, ISCA1P6,ISCU, ISG20, ISLR, ISM1, ISM1-AS1, ISOC1, ITCH, ITGA10, ITGA2, ITGAD,ITGAM, ITGAV, ITGAX, ITGB2, ITGB3, ITGB3BP, ITIH3, ITIH4, ITIH5, ITK,ITM2B, ITPK1-AS1, ITPR2, ITPR3, ITPRIPL2, IZUMO2, J01415.10, J01415.13,J01415.14, J01415.2, J01415.23, J01415.24, J01415.25, J01415.4,J01415.5, J01415.6, J01415.9, JAGN1, JAK1, JAK2, JAKMIP3, JAZF1, JHDM1D,JKAMP, JMJD1C, JMY, JPH1, JRKL, JUNB, KAAG1, KAT2B, KAT7, KATNA1,KB-1047C11.2, KB-1090H4.2, KB-1183D5.11, KB-1208A12.3, KB-1460A1.5,KB-1562D12.3, KB-1592A4.14, KB-1615E4.2, KB- 1639H6.4, KB-1732A1.1,KB-1907C4.2, KB-1980E6.3, KB-431C1.3, KB-431C1.4, KBTBD10, KBTBD2,KBTBD3, KBTBD5, KCMF1, KCNA1, KCNA2, KCNA5, KCNAB1, KCNC1, KCNC4-AS1,KCND3-IT1, KCNE1, KCNE4, KCNF1, KCNG3, KCNH1, KCNH1-IT1, KCNH2, KCNJ10,KCNJ13, KCNJ14, KCNJ15, KCNJ8, KCNJ9, KCNK1, KCNK12, KCNK3, KCNK4,KCNK6, KCNK9, KCNMA1, KCNMB2, KCNMB2-IT1, KCNN4, KCNQ1-AS1, KCTD13,KCTD14, KCTD6, KCTD9, KCTD9P1, KCTD9P2, KDELC2, KDELR2, KDELR3, KDM1B,KDM4D, KDR, KDSR, KHDC1L, KIAA0020, KIAA0146, KIAA0196-AS1, KIAA0226L,KIAA0247, KIAA0319, KIAA0367, KIAA0368, KIAA0408, KIAA0430, KIAA0494,KIAA0672, KIAA0947, KIAA1033, KIAA1107, KIAA1128, KIAA1147, KIAA1274,KIAA1279, KIAA1383, KIAA1407, KIAA1429, KIAA1430, KIAA1524, KIAA1551,KIAA1586, KIAA1598, KIAA1614, KIAA1644, KIAA1704, KIAA1731, KIAA1737,KIAA2018, KIAA2022, KIAA2026, KIF13A, KIF21A, KIF25, KIF26B, KIF27,KIF5B, KIRREL3, KIRREL3-AS2, KLF1, KLF10, KLF11, KLF14, KLF3P1,KLF7-IT1, KLF8, KLF9, KLHDC1, KLHDC5, KLHDC7B, KLHDC8A, KLHL1, KLHL12,KLHL15, KLHL20, KLHL24, KLHL28, KLHL30, KLHL32, KLHL33, KLHL38, KLHL6,KLHL7-AS1, KLHL8, KLK1, KLK11, KLK3, KLKB1, KLRC1, KNG1, KPNA1, KPNA4,KRBOX1, KRBOX1-AS1, KRCC1, KRIT1, KRR1, KRT10, KRT12, KRT13, KRT16P1,KRT16P2, KRT17, KRT18P10, KRT18P16, KRT18P17, KRT18P29, KRT18P37,KRT18P4, KRT18P8, KRT222, KRT28, KRT32, KRT40, KRT78, KRT80, KRT8P10,KRT8P22, KRT8P28, KRT8P30, KRT8P31, KRT8P37, KRT8P41, KRT8P46, KRT8P7,KRT8P9, KRTAP10-1, KRTAP10-10, KRTAP10-2, KRTAP10-7, KRTAP12-1,KRTAP12-3, KRTAP3-2, KRTAP3-3, KRTAP4-3, KRTAP4-4, KRTAP5-4, KRTAP5-8,KTN1, KY, KYNU, L29074.3, L34079.1, LA16c-306A4.1, LA16c-306E5.2,LA16c-306E5.3, LA16c-321D4.1, LA16c- 321D4.2, LA16c-325D7.2,LA16c-390E6.3, LA16c-390H2.4, LA16c-431H6.6, LACC1, LACTB2, LAIR1,LAMA3, LAMB4, LAMC2, LAMP1, LAMP2, LAMP3, LAMTOR3, LAMTOR3P2, LAP3P2,LAPTM4A, LAPTM5, LARP1B, LARP1P1, LARP4, LARP4P, LARP7, LARS, LAT, LAX1,LBP, LCA5, LCA5L, LCE5A, LCMT2, LCN10, LCN2, LCNL1, LCP2, LCT, LDHAL6FP,LDHBP1, LDHBP2, LDHC, LDLRAP1, LEAP2, LECT1, LEMD1-AS1, LEMD3, LEPROTL1,LETMD1, LGALS3, LGALS7B, LGALS8, LGALS9, LGI1, LGI2, LGR5, LGSN, LHFP,LIAS, LIF, LILRA2, LILRA3, LILRB1, LILRB2, LILRB4, LIMCH1, LIMD1, LIMD1-AS1, LIMS1, LIN54, LINC00152, LINC00159, LINC00161, LINC00184,LINC00207, LINC00222, LINC00229, LINC00237, LINC00240, LINC00263,LINC00266-1, LINC00271, LINC00284, LINC00303, LINC00312, LINC00334,LINC00336, LINC00339, LINC00356, LINC00359, LINC00361, LINC00365,LINC00381, LINC00391, LINC00398, LINC00426, LINC00441, LINC00449,LINC00464, LINC00467, LINC00472, LINC00473, LINC00475, LINC00478,LINC00485, LINC00494, LINC00511, LINC00516, LINC00521, LINC00525,LINC00571, LINC00594, LINC00598, LINC00608, LINC00612, LINC00622,LINC00642, LINC00643, LINC00654, LINC00657, LINC00659, LINC00662,LINC00663, LINGO4, LIPH, LIPT1, LIX1L, LL0XNC01-116E7.2, LL0XNC01-131B10.2, LL0XNC01-237H1.3, LL0XNC01-250H12.2, LL0XNC01-250H12.3, LLPH,LMAN1, LMBRD1, LMBRD2, LMCD1, LMNA, LMO1, LMTK2, LNP1, LNPEP, LNX1-AS2,LOC100128731, LOC100129673, LOC100129697, LOC100129913, LOC100130291,LOC100130633, LOC100132060, LOC100132117, LOC100132299, LOC100132444,LOC100133273, LOC100133328, LOC100133600, LOC100133866, LOC100134018,LOC100134188, LOC100144604, LOC133993, LOC144481, LOC145853, LOC146517,LOC147727, LOC154761, LOC203547, LOC283481, LOC284230, LOC284988,LOC285176, LOC285412, LOC339804, LOC387647, LOC388339, LOC388681,LOC389493, LOC390530, LOC392501, LOC399744, LOC399959, LOC400013,LOC401218, LOC401233, LOC440335, LOC440487, LOC440575, LOC440737,LOC441246, LOC641825, LOC642755, LOC643031, LOC643310, LOC643320,LOC643452, LOC643740, LOC644128, LOC644132, LOC645174, LOC645196,LOC645317, LOC645586, LOC645609, LOC646110, LOC646135, LOC646630,LOC647104, LOC647150, LOC647251, LOC647307, LOC649456, LOC650200,LOC650215, LOC650254, LOC650832, LOC652668, LOC652881, LOC653071,LOC653513, LOC653566, LOC653853, LOC654161, LOC728178, LOC728431,LOC728576, LOC728937, LOC729086, LOC729314, LOC729362, LOC729768,LOC730994, LOC731365, LONRF3, LOR, LOXHD1, LPAR4, LPAR6, LPGAT1, LPIN1,LPL, LPP, LRFN2, LRFN5, LRIF1, LRIG1, LRIT3, LRP11, LRP2BP, LRP4,LRP4-AS1, LRP8, LRR1, LRRC15, LRRC16A, LRRC2, LRRC25, LRRC34, LRRC37A,LRRC37A15P, LRRC37A6P, LRRC37B, LRRC37BP1, LRRC39, LRRC3C, LRRC4,LRRC52, LRRC8B, LRRC8C, LRRC8E, LRRCC1, LRRD1, LRRFIP2, LRRIQ3, LRRIQ4,LRRK2, LRRTM3, LRRTM4, LSAMP, LSAMP-AS1, LSG1, LSM3, LSM3P5, LSM5, LSP1,LSP1P2, LTBR, LTF, LTV1, LUC7L2, LURAP1L, LVRN, LXN, LY6K, LY75, LY9,LY96, LYAR, LYN, LYNX1, LYRM2, LYRM5, LYRM7, LYSMD2, LYST-IT1, LYVE1,LZIC, MAB21L3, MAEL, MAFA, MAFIPL, MAGEA11, MAGEE2, MAGOH, MAGOH2,MAGOHB, MAGT1, MAK16, MAL2, MALAT1, MAMDC2, MAN1A1, MAN1A2, MAN1C1,MANEA, MANSC1, MANSC4, MAP1LC3A, MAP1LC3B, MAP1LC3B2, MAP2, MAP2K1,MAP2K1P1, MAP2K3, MAP3K13, MAP3K14, MAP3K14-AS1, MAP3K2, MAP3K5, MAP3K6,MAP3K7, MAP3K8, MAP6D1, MAP7, MAP7D2, MAPK10, MAPK15, MAPK1IP1L, MAPK9,MAPKAPK2, MAPRE1P1, MAPT, MAPT-AS1, MARCO, MARK1, MARK2P8, MARVELD1,MAST4-AS1, MAT1A, MAT2A, MAT2B, MB, MB21D1, MBD2, MBD3L5, MBD4, MBIP,MBL1P, MBLAC2, MBNL1, MBNL2, MBNL3, MBOAT4, MC1R, MCEE, MCF2L2, MCFD2P1,MCHR1, MCMBP, MCMDC2, MCOLN2, MCPH1, MCTP2, MCTS1, MDFIC, MDH1, MDH2,MDM2, ME1, ME2, ME3, MEAF6P1, MED14, MED21, MED4, MED7, MED9, MEF2A,MEFV, MEG3, MEG8, MEG9, MEGF9, MEIG1, MEIOB, MEIS1-AS1, MEIS1-AS2,MEIS2, MEIS3P1, MEPE, MESP1, MESP2, MESTP3, METAP2, Metazoa_SRP, METRNL,METT10D, METTL1, METTL14, METTL15, METTL15P1, METTL16, METTL20,METTL21A, METTL21B, METTL21C, METTL23, METTL5, METTL7A, MFAP1, MFAP1P1,MFAP3L, MFHAS1, MFSD1, MFSD2A, MGARP, MGAT1, MGAT2, MGAT4A, MGAT5,MGC16291, MGC18216, MGC50722, MGEA5, MGP, MIA2, MIA3, MID1, MIER3, MINA,MINOS1P1, MINOS1P3, MINPP1, MIOS, MIOX, MIPEP, MIPEPP3, MIR106B,MIR1185-1, MIR1185-2, MIR1249, MIR1250, MIR1254-1, MIR1255B1, MIR125B2,MIR1290, MIR129-2, MIR1302-11, MIR141, MIR1470, MIR151B, MIR153-1,MIR1538, MIR155HG, MIR181C, MIR181D, MIR185, MIR192, MIR194-2, MIR1974,MIR199B, MIR200A, MIR200B, MIR200C, MIR22HG, MIR23A, MIR23B, MIR24-1,MIR26A2, MIR27A, MIR27B, MIR299, MIR29B2, MIR29C, MIR3116-2, MIR3117,MIR3124, MIR3132, MIR3174, MIR3180-1, MIR3183, MIR3184, MIR3188,MIR3189, MIR3192, MIR3202-2, MIR320B2, MIR331, MIR342, MIR34A, MIR3605,MIR3613, MIR367, MIR3671, MIR3680-1, MIR3680-2, MIR3682, MIR369,MIR3692, MIR370, MIR374A, MIR376A1, MIR377, MIR378D2, MIR3916, MIR3918,MIR3926-2, MIR3929, MIR3935, MIR3944, MIR3945, MIR409, MIR410, MIR412,MIR4258, MIR4263, MIR4284, MIR429, MIR4319, MIR4426, MIR4458, MIR4461,MIR4484, MIR4489, MIR4492, MIR4512, MIR4515, MIR4523, MIR4526, MIR4534,MIR455, MIR4635, MIR4638, MIR4642, MIR4653, MIR4656, MIR4665, MIR4669,MIR4672, MIR4682, MIR4685, MIR4689, MIR4701, MIR4712, MIR4714, MIR4728,MIR4729, MIR4740, MIR4754, MIR4761, MIR4786, MIR4787, MIR493, MIR499A,MIR5001, MIR5188, MIR5191, MIR5196, MIR541, MIR548AN, MIR548D2, MIR548U,MIR5587, MIR559, MIR568, MIR5695, MIR5698, MIR5699, MIR572, MIR574,MIR575, MIR589, MIR597, MIR609, MIR639, MIR642A, MIR654, MIR655, MIR656,MIR659, MIR665, MIR670, MIR708, MIR7- 3, MIR758, MIR769, MIR770, MIR99B,MIRLET7DHG, MIS12, MIS18BP1, MITD1, MK167IP, MKLN1, MKRN2, MKRN2-AS1,MKRN4P, MKX, MLC1, MLIP, MLIP-AS1, MLKL, MLLT10P1, MLNR, MLPH, MMAA,MMADHC, MMP1, MMP3, MMP7, MMRN1, MNAT1, MNS1, MNX1, MOB1A, MOBKL1B,MOBP, MOCOS, MOCS2, MON2, MORC3, MORF4, MORF4L1P1, MORF4L2, MORN2,MOSC2, MOSPD2, MOV10L1, MPC1, MPC1L, MPEG1, MPHOSPH10, MPHOSPH8, MPLKIP,MPP1, MPP5, MPP6, MPP7, MPRIP-AS1, MPV17, MPV17L, MR1, MRAP2, MRC1,MRE11A, MRFAP1L1, MRGPRE, MRO, MRPL1, MRPL18, MRPL19, MRPL24, MRPL3,MRPL32, MRPL33, MRPL39, MRPL3P1, MRPL42, MRPL46, MRPL48, MRPL50, MRPS10,MRPS15P2, MRPS23, MRPS29P2, MRPS30, MRPS31, MRPS31P3, MRPS31P4, MRPS33,MRPS36, MRPS5P3, MS4A10, MS4A14, MS4A4A, MS4A6A, MS4A7, MSANTD4, MSI2,MSL2, MSMO1, MSR1, MST4, MSTN, MSX1, MT1A, MT1B, MT1DP, MT1E, MT1F,MT1G, MT1H, MT1JP, MT1L, MT1M, MT1P1, MT1P3, MT1X, MT1XP1, MT2A, MT4,MT-ATP6, MTBP, MT-CO1, MT-CO2, MT-CYB, MTDH, MTE, MTERF, MTERFD1, MTF1,MTHFD1, MTHFD1P1, MTIF2, MTIF3, MTMR2, MTMR6, MTMR8, MTND1P23, MT-ND2,MTND2P28, MT-ND3, MTND3P10, MT-ND4, MT-ND4L, MTND4P10, MTND4P11,MTND4P14, MTND4P15, MTND4P24, MTND4P26, MT-ND5, MTND5P19, MTND5P28, MT-ND6, MTO1, MTPN, MTRNR2L3, MTRNR2L4, MTRNR2L8, MTRNR2L9, MTRR, MTUS1,MTUS2-AS1, MTX3, MUC12, MUC13, MUC17, MUSTN1, MVP, MX1, MXD1, MXI1,MXRA7, MYADML, MYBL1, MYCBP2, MYCT1, MYH11, MYH15, MYH6, MYH7, MYL3,MYLIP, MYLK3, MYLPF, MYNN, MYO1D, MYO1F, MYO3A, MYO3B, MYO5A, MYO5BP1,MYOCD, MYOF, MYOM1, MYOT, MYPN, MZT1, N4BP2L1, N4BP2L2, NAA15, NAA20,NAA25, NAA30, NAA35, NAA50, NAALAD2, NAALADL2, NAB1, NACA2, NACA3P,NACAP1, NADKD1, NALCN, NALCN-AS1, NAMPT, NAMPTL, NANOS2, NANP, NANS,NAP1L1P1, NAP1L1P2, NAP1L1P3, NAP1L2, NAP1L4P3, NAP1L5, NAPEPLD, NAPG,NARS, NAT16, NAT8, NAV2, NAV2-AS1, NAV2-AS2, NAV2-AS3, NBEAP1, NBL1,NBN, NBPF11, NBPF14, NBPF24, NBPF7, NBR1, NCAPG, NCAPG2, NCBP1, NCBP2,NCBP2L, NCEH1, NCF1, NCF1C, NCF2, NCF4, NCK1, NCKAP1, NCKAP1L, NCMAP,NCOA2, NCOA3, NCOA4, NCR1, NCR3LG1, NCRNA00200, NDEL1, NDFIP1, NDFIP2,NDRG1, NDUFA4, NDUFA5, NDUFAB1, NDUFAF1, NDUFAF2, NDUFAF4, NDUFAF5,NDUFB3, NDUFC2, NDUFS4, NDUFV2, NEAT1, NECAB1, NECAP1P1, NEDD4, NEFH,NEFHP1, NEIL2, NEK1, NEK10, NEK4, NELF, NELL2, NEO1, NET1, NEUROD2,NEXN, NEXN-AS1, NFAM1, NFE2L2, NFIA, NFIC, NFIL3, NFIX, NFKBIA, NFS1,NFU1, NFX1, NGEF, NGF, NGLY1, NHEJ1, NHLH2, NHLRC1, NHLRC3, NID1,NIF3L1, NIN, NIPAL1, NIPAL4, NIPBL, NIPSNAP3B, NKAP, NKAPL, NKIRAS1,NKRF, NKX2-2, NKX2-2-AS1, NKX2-3, NKX3-1, NKX3-2, NKX6-1, NLF2, NLGN1,NLK, NLRC4, NLRC5, NLRP2, NLRP9, NMD3, NMD3P1, NME2P1, NME5, NME7, NMI,NMNAT2, NMRK1, NMUR1, NMUR2, NNMT, NOC3L, NOL10, NOL3, NOL4, NOL7, NOL8,NOLC1, NOP58, NOSTRIN, NOTCH2NL, NOTO, NOV, NOX5, NOXRED1, NPAS2, NPAS4,NPAT, NPBWR1, NPC1, NPL, NPM1P18, NPM1P21, NPM1P6, NPPC, NPS, NPTN,NPTX2, NPVF, NPY, NPY6R, NQO1, NQO2, NR0B1, NR1D2, NR1H2, NR1I2,NR2C2AP, NR2E3, NR3C1, NR3C2, NR4A2, NR4A3, NR5A2, NRCAM, NRD1, NRG1,NRG1-IT1, NRG2, NRG3-AS1, NRG4, NRIP1, NRIP3, NRP2, NRSN1, NSA2, NSF,NSFP1, NSL1, NSMAF, NSMCE1, NSRP1, NSUN2, NSUN3, NSUN6, NT5C1B, NT5CP1,NTPCR, NTRK1, NUAK2, NUB1, NUCB2, NUCKS1, NUDCD2, NUDT12, NUDT19,NUDT21, NUDT22, NUDT3, NUDT4, NUDT4P1, NUDT6, NUDT7, NUDT9, NUFIP1,NUFIP1P, NUFIP2, NUGGC, NUP107, NUP155, NUP35, NUP62CL, NUP98, NUPL1,NUPR1, NUPR1L, NUS1, NUS1P1, NWD1, NXF2B, NXF5, NXNL1, NXPE3, NXT1,NXT2, NYAP2, O3FAR1, OAF, OAS2, OAS3, OASL, OAT, OBFC1, OCIAD1,OCIAD1-AS1, OCLM, OCM2, ODC1, ODF4, OFD1P17, OGDHL, OGFOD1, OGFOD1P1,OGN, OGT, OIP5, OIP5-AS1, OLFM1, OLFM4, OLIG1, OLIG2, OLIG3, OLR1, OMA1,OMD, OMG, OMP, OPA1, OPALIN, OPRD1, OPTC, OR10AC1P, OR10AD1, OR10H1,OR10H5, OR13A1, OR1F12, OR1L3, OR1L8, OR1Q1, OR2A13P, OR2L13, OR3A3,OR3B1P, OR4A46P, OR4K13, OR4N2, OR4X2, OR52B3P, OR5B2, OR5K2, OR6D1P,OR6E1P, OR7D2, OR7E154P, OR7E91P, OR7L1P, OR8S1, OR8T1P, OR9A1P, OR9A3P,OR9M1P, ORC2, ORC3, ORC3L, ORC4, ORC5, ORMDL1, orphan, OSBP, OSBPL3,OSBPL6, OSBPL8, OSCAR, OSGEPL1, OSGIN2, OSM, OSMR, OSTC, OSTCP1, OSTCP2,OSTCP4, OSTCP5, OSTCP6, OSTF1, OSTF1P1, OSTM1, OTOGL, OTUD1, OTUD3,OTUD4, OTUD6B, OTUD7B, OVOL2, OVOL3, OXCT2, OXCT2P1, OXGR1, OXNAD1,OXR1, OXSM, OXTR, P2RX2, P2RX5, P2RX6, P2RX7, P2RY1, P2RY13, P2RY5,P4HA1, P4HA3, PA2G4P2, PA2G4P4, PABPC1P1, PABPC1P10, PABPC1P11, PACRGL,PACSIN2, PAFAH1B2, PAICSP4, PAIP2, PAK1IP1, PAK3, PALM2, PALM2-AKAP2,PALMD, PAM, PAN2, PAN3-AS1, PAPD5, PAPOLA, PAPPA2, PAPSS2, PAQR3,PARD3B, PARM1, PARP10, PARP12, PARP14, PARP15, PARP1P1, PARP8, PARP9,PART1, PARVA, PARVB, PARVG, PATE1, PATE4, PATL1, PATL2, PAX5, PAX6,PAX9, PBLD, PCA3, PCDH17, PCDH20, PCDH7, PCDHA3, PCDHAC1, PCDHB1,PCDHB11, PCDHB13, PCDHB18, PCDHB3, PCDHGA1, PCDHGA11, PCDHGA12, PCDHGA2,PCDHGA3, PCDHGA4, PCDHGA5, PCDHGA6, PCDHGA8, PCDHGA9, PCDHGB1, PCDHGB2,PCDHGB3, PCDHGC3, PCGF1, PCGF5, PCK1, PCLO, PCM1, PCMTD1P3, PCNA, PCNP,PCNPP5, PCSK1, PCSK2, PCYOX1, PDCD1, PDCD10, PDCD1LG2, PDCD4, PDCD6IP,PDCL, PDE10A, PDE12, PDE1B, PDE3A, PDE4D, PDE4DIP, PDE7B, PDE8A, PDE8B,PDGFRL, PDIA3, PDIA3P, PDIA4, PDIA6, PDK4, PDLIM1, PDLIM5, PDP2, PDPK2,PDS5A, PDX1, PDX1-AS1, PDZD8, PDZD9, PEA15, PEAR1, PEBP1, PEG3, PELO,PEMT, PER3, PERP, PET117, PEX1, PEX11A, PEX12, PEX13, PEX2, PEX3,PEX5L-AS1, PEX7, PFKFB2, PFN1P2, PFN1P7, PFN2, PFTK1, PGAM1P11, PGAM1P7,PGAM4P1, PGBD3, PGBD4P3, PGBD4P7, PGBD5, PGDP1, PGM2, PGM3, PGM5P1,PGPEP1L, PGR, PGRMC2, PHACTR2, PHBP1, PHBP15, PHBP4, PHEX, PHEX-AS1,PHF1, PHF10, PHF11, PHF15, PHF17, PHF6, PHGR1, PHKA1, PHKA1P1, PHLDA3,PHLPP2, PHOSPHO2, PHTF2, PHYHIP, PHYHIPL, PI15, PI3, PIAS2, PIBF1,PICALM, PIGA, PIGB, PIGC, PIGF, PIGH, PIGK, PIGN, PIGP, PIGR, PIGV,PIGY, PIK3C2A, PIK3C2G, PIK3CA, PIK3CB, PIK3R6, PINX1, PION, PIR, PIRT,PITHD1, PITPNC1, PIWIL2, PJA2, PKDREJ, PKHD1, PKIB, PKN2, PKP2, PKP4,PKP4P1, PLA1A, PLA2G12A, PLA2G12AP1, PLA2G1B, PLA2G2C, PLA2G2E, PLA2G4A,PLA2G4C, PLA2G7, PLAA, PLAC9, PLAGL1, PLAT, PLAU, PLAUR, PLB1, PLBD1,PLCB1, PLCB4, PLCE1, PLCH2, PLCL2, PLCL2-AS1, PLCXD3, PLCZ1, PLD1, PLD6,PLEK, PLEK2, PLEKHA1, PLEKHA2, PLEKHA3, PLEKHA8P1, PLEKHB2, PLEKHF2,PLEKHH2, PLEKHM2, PLEKHN1, PLEKHS1, PLGLB1, PLGRKT, PLIN5, PLOD2, PLP2,PLS1, PLSCR1, PLSCR2, PLVAP, PM20D1, PMCH, PMM2, PMS1, PNLIP, PNLIPRP1,PNLIPRP2, PNMA2, PNO1, PNP, PNPLA2, PNPLA5, PNPLA8, PNPO, PNRC1, PNRC2,POC1B, POC5, POF1B, POGK, POLD3, POLE3, POLE4, POLG2, POLH, POLK, POLQ,POLR1D, POLR2B, POLR2C, POLR2J2, POLR2K, POLR3B, POLR3G, POLR3GL, POMC,POMP, PON3, POP5, POP7, POPDC3, POT1, POTEG, POU2AF1, POU4F1-AS1, PP2D1,PPA1, PPA2, PPAPDC1B, PPBP, PPCDC, PPCS, PPIAP13, PPIAP14, PPIAP2,PPIAP20, PPIAP3, PPIEL, PPIG, PPIL4, PPIL6, PPIP5K1, PPM1A, PPM1E,PPM1H, PPM1K, PPME1, PPP1CB, PPP1R11, PPP1R14C, PPP1R15B, PPP1R1A,PPP1R1C, PPP1R2, PPP1R27, PPP1R2P3, PPP1R2P6, PPP1R36, PPP1R3C, PPP1R3D,PPP2CA, PPP2CB, PPP2R1B, PPP2R2C, PPP2R5A, PPP2R5E, PPP3CC, PPP3R1,PPP6C, PPT1, PQLC3, PRAMEF19, PRB4, PRDM1, PRDM4, PRDX1, PRDX3P1, PRDX4,PRELID1P2, PRELID1P4, PRELP, PREPL, PREX1, PRG2, PRG4, PRICKLE2-AS3,PRICKLE3, PRIM2, PRIMA1, PRINS, PRKAB2, PRKACB, PRKAG2-AS1, PRKCA,PRKCE, PRKCH, PRKRIR, PRKRIRP1, PRKRIRP6, PRKRIRP7, PRKRIRP8, PRKRIRP9,PRKX, PRL, PRMT10, PRNP, PROCR, PROK2, PROP1, PRORSD1P, PROSC,PROX1-IT1, PRPF18, PRPF38B, PRPF4, PRPF40A, PRPF6, PRPH, PRPH2, PRPS1L1,PRPS2, PRR13, PRR16, PRRC1, PRRC2A, PRRT1, PRRT3, PRRX2, PRSS1, PRSS23,PRSS3, PRSS3P1, PRSS3P2, PRSS41, PRSS48, PRSS51, PRSS55, PRSS58, PRUNE,PRUNE2, PSAT1P3, PSCA, PSG4, PSG5, PSG9, PSMA1, PSMA2P1, PSMA2P3, PSMA3,PSMA4, PSMA6, PSMA6P2, PSMB1, PSMB10, PSMB8, PSMC1P1, PSMC1P10, PSMC1P5,PSMC1P9, PSMC2, PSMC3, PSMC3IP, PSMC6, PSMD1, PSMD10, PSMD10P2, PSMD12,PSMD14, PSMD6, PSME2P2, PSMG1, PSMG2, PSPC1-OT1, PSPHP1, PTAFR, PTAR1,PTBP3, PTCD2, PTCHD3, PTCHD4, PTDSS1, PTEN, PTENP1, PTER, PTGDS,PTGER4P2, PTGES3, PTGES3P1, PTGES3P2, PTGES3P3, PTGES3P4, PTGFR, PTGIR,PTGR1, PTGS1, PTGS2, PTH2R, PTHLH, PTK2, PTMAP3, PTP4A1P6, PTP4A2P1,PTPDC1, PTPN11, PTPN13, PTPN20A, PTPN20B, PTPN22, PTPN2P1, PTPN3, PTPN4,PTPN7, PTPRC, PTPRE, PTPRH, PTPRJ, PTRH2, PTX3, PURA, PURB, PUS10, PUS3,PUS7L, PVRIG, PVRL3, PVRL3-AS1, PVT1, PWWP2AP1, PWWP2B, PXDC1, PXK,PYDC1, PYGL, PYGM, PYGO1, PYROXD1, PYURF, PYY2, QPCT, QRFP, QRSL1P1,QTRTD1, R3HCC1L, RAB10, RAB11FIP1, RAB11FIP5, RAB12, RAB14, RAB18,RAB1A, RAB21, RAB22A, RAB23, RAB24, RAB27A, RAB2A, RAB30, RAB31, RAB33B,RAB39B, RAB3GAP1, RAB3GAP2, RAB3IP, RAB40A, RAB40AL, RAB42, RAB5A,RAB6A, RAB7L1, RAB9A, RAB9B, RABEP1, RABGAP1L, RABGEF1, RABGGTB, RABL3,RAD17, RAD18, RAD50, RAD51AP2, RAD51C, RAD54B, RAET1E, RAET1G, RAET1K,RAG1, RAI1-AS1, RALGAPA1P, RALGAPB, RAMP3, RANBP2, RANBP3L, RANBP6,RANBP9, RANGAP1, RAP1A, RAP1B, RAP1GDS1, RAPH1, RARRES1, RARRES3, RARS,RASA2, RASAL3, RASD1, RASD2, RASGEF1A, RASGRF1, RASGRF2, RASGRP1,RASGRP3, RASL12, RASSF5, RASSF6, RASSF8, RAX, RAX2, RB1, RBBP4P1,RBBP4P2, RBBP5, RBBP8, RBFOX1, RBKS, RBL2, RBM11, RBM12B, RBM12B-AS2,RBM15, RBM18, RBM20, RBM26-AS1, RBM27, RBM43, RBM45, RBM47, RBMX2P3,RBP4, RBP7, RBPJL, RBPMSLP, RC3H2, RCAN2, RCBTB2, RCC2P4, RCC2P7, RCHY1,RCSD1, RDH10, RDH14, RDX, RECQL, REEP5, REG1A, REG1B, REG1P, REG3A,REG3G, RELB, REN, REP1, REPS2, RERGL, REXO2, RFC1, RFC3, RFC4, RFC5,RFESD, RFESDP1, RFFL, RFKP1, RFPL3, RFPL3-AS1, RFTN1, RFX6, RFX8, RGCC,RGL1, RGN, RGPD1, RGPD5, RGPD8, RGS1, RGS10, RGS16, RGS17, RGS17P1,RGS20, RGS22, RGS5, RGS7BP, RGS9, RGS9BP, RHBDD1, RHCG, RHD, RHEB,RHEBL1, RHOBTB1, RHOBTB3, RHOJ, RHOQ, RHOQP1, RHOQP2, RHOQP3, RHOT1,RHOT1P1, RHOT1P3, RIBC2, RIC8B, RICH2, RIIAD1, RILP, RIMBP3B, RIMBP3C,RIMKLBP1, RIN1, RIN2, RIN3, RINL, RINT1, RIOK1, RIOK2, RIPK2, RIPK3,RIPPLY1, RIPPLY2, RLF, RLIM, RLIMP1, RLIMP2, RLN1, RLN2, RLN3, RMND1,RMND5A, RN7SL1, RNA5SP108, RNA5SP118, RNA5SP122, RNA5SP132, RNA5SP162,RNA5SP18, RNA5SP187, RNA5SP203, RNA5SP217, RNA5SP219, RNA5SP261,RNA5SP262, RNA5SP263, RNA5SP265, RNA5SP33, RNA5SP370, RNA5SP383,RNA5SP429, RNA5SP450, RNA5SP462, RNA5SP494, RNA5SP496, RNA5SP53,RNase_MRP, RNASE1, RNASE2, RNASE6, RNASEH1P2, RNASEH2B, RNASEH2CP1,RNASEL, RNF103, RNF114, RNF13, RNF130, RNF133, RNF135, RNF138P1, RNF14,RNF141, RNF145, RNF148, RNF168, RNF169, RNF180, RNF183, RNF186, RNF19A,RNF19B, RNF2, RNF216-IT1, RNF219, RNF223, RNF32, RNF6, RNFT1, RNGTT,RNLS, RNU12-2P, RNU1-5, RNU2-5P, RNU2-6P, RNU2- 79, RNU4-1, RNU4-8P,RNU5A-1, RNU6-10, RNU6-2, RNU6-33, RNU6-42, RNU6-45, RNU6-8, RNU6V,RNU7-3P, RNU7-47P, RNU7-71P, RNY1, RNY1P6, RNY3, RNY4P26, RNY4P4,RNY4P6, ROBO2, ROCK1, ROCK2, ROPN1B, ROPN1L, RORA, RORC, RP1-102E24.8,RP1-102E24.9, RP1-102K2.6, RP11- 1006G14.1, RP11-1006G14.2,RP11-1008C21.1, RP11-100A13.1, RP11-100G15.10, RP11-100G15.3,RP11-100L22.2, RP11-1016B18.1, RP11-1017G21.3, RP11- 1018J11.1,RP11-101E13.1, RP11-101E7.2, RP11-101P17.11, RP11-101P17.6,RP11-1026M7.2, RP11-1029J19.5, RP11-102F4.2, RP11-102F4.3,RP11-102H24.1, RP11-102L12.2, RP11-102M11.1, RP11-1033A18.1,RP11-104L21.2, RP11- 104O19.2, RP11-1055B8.3, RP11-105C20.1,RP11-1060G2.1, RP11-1060J15.4, RP11-106M3.1, RP11-106M7.1,RP11-1070A24.1, RP11-1074O12.1, RP11- 1079K10.2, RP11-107I14.2,RP11-107M16.2, RP11-1084A12.1, RP11-1084A12.2, RP11-1084J3.1,RP11-108B14.4, RP11-108M9.4, RP11-108M9.5, RP11-108O10.2, RP11-1090M7.1,RP11-1090M7.2, RP11-1094M14.7, RP11-1096G20.5, RP11- 109A6.4,RP11-109D9.3, RP11-109D9.4, RP11-109E24.2, RP11-109G23.3, RP11- 10J21.3,RP11-10J21.4, RP11-10K16.1, RP11-10L12.4, RP11-10L7.1, RP11- 10N16.3,RP11-10N23.2, RP11-10O22.2, RP11-1101H11.1, RP11-1102P16.1, RP11-1103G16.1, RP11-1105G2.3, RP11-1105G2.4, RP11-110H1.2, RP11-110H10.2,RP11-110I1.5, RP11-110J1.2, RP11-1112C15.1, RP11-1112J20.1,RP11-1112J20.2, RP11-1113L8.6, RP11-1114I9.1, RP11-111A21.1,RP11-111A22.1, RP11-111E14.1, RP11-111F16.2, RP11-111K18.2,RP11-1124B17.1, RP11-112H10.4, RP11- 1134I14.3, RP11-1134I14.8,RP11-1136G11.6, RP11-113D6.10, RP11-113D6.6, RP11-113K21.2,RP11-1140I5.1, RP11-114B7.6, RP11-114F10.2, RP11-114F10.3, RP11-114F3.2,RP11-114F3.5, RP11-114H24.4, RP11-114H24.6, RP11-114L10.2, RP11-114M5.1,RP11-115C10.1, RP11-115D19.1, RP11-115H15.1, RP11-115L11.1,RP11-115N12.1, RP11-1166P10.9, RP11-1167A19.2, RP11-116O18.1, RP11-117F22.1, RP11-117L5.4, RP11-118D22.3, RP11-118E18.4, RP11-118M9.3,RP11- 119B16.2, RP11-119D9.1, RP11-119F7.2, RP11-119N19.1,RP11-120C12.3, RP11- 120M18.2, RP11-1212A22.2, RP11-121L10.3,RP11-121P10.1, RP11-122A3.2, RP11-122C9.1, RP11-122F14.3, RP11-123B3.6,RP11-123C21.1, RP11-123J14.2, RP11-123M6.2, RP11-124A7.2, RP11-124D2.3,RP11-124D2.6, RP11-125H8.1, RP11-125I23.3, RP11-125K10.4,RP11-1260E13.4, RP11-126O1.4, RP11-127B16.1, RP11-127L20.6,RP11-1280I22.1, RP11-128A17.1, RP11-128A6.2, RP11-128A6.3, RP11-128M1.1,RP11-1299A16.3, RP11-129B22.2, RP11-129B22.6, RP11-129B9.1,RP11-129K20.2, RP11-12A1.1, RP11-12C17.2, RP11-12D24.6, RP11-12M5.4,RP11-12M9.4, RP11-131H24.4, RP11-131K5.1, RP11-1334A24.6, RP11-133K1.6,RP11-133L14.4, RP11-133O22.6, RP11-1348G14.1, RP11-1348G14.4, RP11-1348G14.5, RP11-134E15.2, RP11-134G8.7, RP11-134G8.8, RP11-134L4.1,RP11- 134P9.1, RP11-135A24.2, RP11-135F9.1, RP11-135J2.3, RP11-137H2.4,RP11- 137L10.5, RP11-137N23.1, RP11-138I1.3, RP11-139I14.2,RP11-139J15.2, RP11- 13G14.4, RP11-13J8.1, RP11-13L2.2, RP11-13N13.5,RP11-13N13.6, RP11- 140A10.3, RP11-1415C14.4, RP11-141J13.4,RP11-142G7.2, RP11-142J21.2, RP11- 142L4.3, RP11-142M10.2, RP11-142O6.1,RP11-143E21.7, RP11-143M1.3, RP11- 144A16.1, RP11-144G7.2, RP11-144L1.2,RP11-144L1.8, RP11-144N1.1, RP11- 145M4.3, RP11-145M9.3, RP11-146E13.3,RP11-146F11.4, RP11-147I3.1, RP11- 147O5.1, RP11-149I2.4, RP11-149I9.2,RP11-14I17.1, RP11-150L8.3, RP11- 151D14.1, RP11-151G12.2, RP11-151H2.3,RP11-152F13.1, RP11-152F13.2, RP11- 152F13.4, RP11-152F13.5,RP11-152H18.4, RP11-152K4.2, RP11-152N13.5, RP11- 153F1.1,RP11-154B12.3, RP11-154P18.1, RP11-154P18.2, RP11-155G14.5, RP11-155G15.2, RP11-156E6.1, RP11-156K13.2, RP11-156L14.1, RP11-156N15.1,RP11- 157G21.2, RP11-157L3.4, RP11-158I9.5, RP11-158I9.7, RP11-158M2.2,RP11- 158M2.4, RP11-158N24.1, RP11-159A18.1, RP11-159C21.4,RP11-159F24.3, RP11- 159H10.3, RP11-159H22.1, RP11-159H3.1,RP11-159J3.1, RP11-15A1.3, RP11- 15E18.1, RP11-15F12.1, RP11-15I11.3,RP11-160C18.2, RP11-160E2.6, RP11- 160H12.2, RP11-160H22.3,RP11-160N1.10, RP11-160O5.1, RP11-161E22.2, RP11- 161H23.11,RP11-161H23.5, RP11-161H23.9, RP11-162D9.3, RP11-162G10.4,RP11-162G10.5, RP11-162G9.1, RP11-162J8.3, RP11-163E9.1, RP11-163E9.2,RP11-163F15.1, RP11-164C1.2, RP11-164N3.3, RP11-165F24.2, RP11-165F24.5,RP11-165H4.2, RP11-165N19.2, RP11-166A12.1, RP11-166B2.5, RP11-166B2.7,RP11-166B2.8, RP11-166D19.1, RP11-166N17.3, RP11-166O4.1, RP11-166P13.4,RP11-167H9.3, RP11-167H9.4, RP11-167H9.6, RP11-167N4.5, RP11-167P20.1,RP11-167P22.3, RP11-168G16.1, RP11-168L22.2, RP11-169D4.1, RP11-169E6.1,RP11-169K16.4, RP11-169K16.6, RP11-169K16.7, RP11-169L17.5, RP11-169O17.5, RP11-16C1.1, RP11-16C18.3, RP11-16E18.3, RP11-16F15.1, RP11-16K12.1, RP11-16L14.2, RP11-16M8.2, RP11-16N11.2, RP11-16P6.1, RP11-170L3.4, RP11-170L3.8, RP11-170M17.1, RP11-171I2.1, RP11-172E9.2, RP11-172F4.2, RP11-172F4.5, RP11-173A6.2, RP11-173B14.5, RP11-173D9.5, RP11-173E2.1, RP11-173M1.4, RP11-174G6.1, RP11-174O3.1, RP11-175B9.3, RP11-175O19.4, RP11-175P19.2, RP11-177H13.2, RP11-178A10.1, RP11-178C3.2,RP11- 178C3.3, RP11-178D12.1, RP11-178F10.2, RP11-178H8.3, RP11-179A7.2,RP11- 179G5.1, RP11-179G5.4, RP11-179H18.7, RP11-179H18.8, RP11-17A1.3,RP11- 17A4.1, RP1-117B12.4, RP11-17E2.2, RP11-17J14.2, RP11-17L5.2,RP11-17L5.4, RP11-17M16.2, RP1-117O3.2, RP11-180O5.2, RP11-181C21.4,RP11-181C3.1, RP11-181E22.1, RP11-181G12.4, RP11-181K3.4, RP11-182B22.2,RP11-182I10.4, RP11-182J23.1, RP11-182L21.4, RP11-183C12.1,RP11-184E9.1, RP11-184E9.2, RP11-184I16.3, RP11-184I16.4, RP11-184M15.1,RP11-184M15.2, RP11-185N2.1, RP11-186F10.2, RP11-187A9.3, 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RP4-791M13.5, RP4-794H19.1, RP4-794H19.2, RP4-797C5.2, RP4-798A10.4, RP4-798C17.6, RP4-799P18.3, RP4-799P18.4, RP4-800M22.1, RP4-803A2.1, RP4-803A2.2, RP4-803J11.2, RP4-805N21.1, RP4-811H24.9, RP4-814D15.1, RP4-814D15.2, RP4-816N1.7, RP5-1002M8.4, RP5-1007M22.2, RP5-1018A4.3, RP5-1021I20.1, RP5-1021I20.2, RP5-1022P6.3,RP5- 1022P6.7, RP5-1024G6.5, RP5-1024G6.7, RP5-1024N4.1, RP5-1028L10.1,RP5- 1029K10.2, RP5-1031J8.1, RP5-1033H22.2, RP5-1043L13.1,RP5-1044H5.1, RP5- 1044H5.2, RP5-1047A19.6, RP5-1050D4.5, RP5-1051J4.4,RP5-1053E7.1, RP5- 1053E7.3, RP5-1055C14.6, RP5-1056L3.3, RP5-1063M23.2,RP5-1067M6.3, RP5- 1068H6.3, RP5-1073O3.7, RP5-1077I2.3, RP5-1086D14.1,RP5-1091N2.2, RP5- 1104E15.6, RP5-1109J22.1, RP5-1115A15.1,RP5-1119A7.14, RP5-1121A15.3, RP5-1121A15.4, RP5-1121E10.2,RP5-1125M8.5, RP5-1142J19.1, RP5-1142J19.2, RP5-1148A21.3,RP5-1157M23.2, RP5-1160K1.1, RP5-1160K1.3, RP5-1160K1.8, RP5-1170D6.1,RP5-1173A5.1, RP5-1178H5.2, RP5-1185H19.2, RP5-1185K9.1, RP5-1198O20.4,RP5-817C23.1, RP5-823G15.5, RP5-836J3.1, RP5-837J1.2, RP5- 837M10.1,RP5-837M10.4, RP5-837O21.2, RP5-855F14.1, RP5-857K21.10, RP5- 857K21.14,RP5-857K21.3, RP5-857K21.4, RP5-862P8.2, RP5-867C24.1, RP5- 874C20.3,RP5-875H18.4, RP5-882O7.4, RP5-882O7.5, RP5-884G6.2, RP5- 886K2.1,RP5-886K2.3, RP5-894A10.2, RP5-905N1.2, RP5-907D15.3, RP5- 919F19.5,RP5-924G13.2, RP5-931E15.2, RP5-931K24.3, RP5-934G17.2, RP5- 934G17.6,RP5-937E21.8, RP5-940J5.3, RP5-940J5.8, RP5-943J3.1, RP5-951N9.1,RP5-956O18.2, RP5-961K14.1, RP5-963E22.4, RP5-968D22.1, RP5-978I12.1,RP5- 981L23.1, RP5-983H21.3, RP5-983L19.1, RP5-983L19.2, RP5-991C6.4,RP5- 991G20.2, RP5-991O23.1, RP5-995J12.2, RP5-997D16.2, RP5-998N21.4,RP6- 109B7.2, RP6-109B7.3, RP6-109B7.4, RP6-11O7.2, RP6-186E3.1,RP6-191P20.4, RP6-201G10.2, RP6-227L5.2, RP6-65G23.1, RPA1, RPA2, RPA3,RPA4, RPAP2, RPAP3, RPE, RPF1, RPF2, RPF2P1, RPH3AL, RPIA, RPL10AP2,RPL11P5, RPL12L3, RPL12P9, RPL13, RPL13AP17, RPL13AP6, RPL13AP7,RPL13P12, RPL15, RPL15P2, RPL15P20, RPL17P1, RPL17P26, RPL18AP2,RPL18P10, RPL18P11, RPL19, RPL19P21, RPL21, RPL21P28, RPL21P3, RPL22,RPL22P11, RPL23, RPL23AP53, RPL23P2, RPL24, RPL26, RPL26P30, RPL26P37,RPL27AP, RPL29P11, RPL29P24, RPL31P2, RPL31P58, RPL31P63, RPL31P7,RPL34, RPL34P23, RPL34P31, RPL35AP26, RPL35AP30, RPL36AL, RPL36AP43,RPL36AP45, RPL36P2, RPL37AP8, RPL37P2, RPL39, RPL39P3, RPL39P40, RPL3L,RPL3P12, RPL5, RPL5P29, RPL7, RPL7AP14, RPL7AP26, RPL7AP34, RPL7AP65,RPL7AP8, RPL7L1P8, RPL7L1P9, RPL7P57, RPL8P2, RPL9P5, RPL9P9, RPN1,RPP25, RPP30, RPS10P16, RPS10P18, RPS10P2, RPS10P7, RPS11P6, RPS13,RPS15AP40, RPS15P9, RPS17, RPS17P2, RPS18P9, RPS19BP1, RPS20P2,RPS20P35, RPS23P8, RPS24, RPS24P17, RPS26P47, RPS27A, RPS27AP1,RPS27AP2, RPS27L, RPS27P27, RPS2P41, RPS2P44, RPS2P45, RPS2P48, RPS3A,RPS3AP26, RPS3AP34, RPS3AP35, RPS3AP39, RPS3AP44, RPS3AP47, RPS3AP5,RPS3AP6, RPS3P1, RPS3P7, RPS4XP16, RPS4XP17, RPS4XP19, RPS4XP22, RPS4Y1,RPS6, RPS6KC1, RPS6P16, RPS6P21, RPS7P2, RPS8P3, RPSAP4, RPSAP47,RPSAP56, RQCD1, RRAD, RRAGC, RRAGD, RRAS2, RRH, RRM1, RRM1-AS1, RRM2B,RRN3, RRP12, RSBN1, RSL24D1, RSL24D1P1, RSL24D1P11, RSL24D1P3, RSPH10B2,RSPH6A, RSPO1, RSPO2, RSU1, RTBDN, RTN3P1, RTN4, RTN4IP1, RTP4, RUFY4,RUNDC3B, RUNX1, RUNX2, RUNX3, RUVBL1-AS1, RWDD1, RWDD4, RWDD4P2, RXFP3,RXRB, RXRG, RYBP, RYR2, S100A11, S100A12, S100A2, S100A3, S100A5,S100A8, S100A9, S100B, S1PR1, SACM1L, SACS-AS1, SAMD11, SAMD3, SAMD4B,SAMD8, SAMD9, SAMD9L, SAMSN1, SAMSN1-AS1, SAP30, SAR1A, SAR1B, SASH3,SASS6, SAT1, SATB1, SAV1, SAYSD1, SBDS, SBDSP1, SBNO2, SBSN, SC5DL,SCAF11, SCAMP1, SCARB2, SCARF1, SCARNA11, SCARNA13, SCARNA20, SCARNA21,SCARNA6, SCARNA7, SCARNA8, SCARNA9, SCD, SCD5, SCDP1, SCEL-AS1, SCFD1,SCFD2, SCG2, SCG3, SCG5, SCGB1A1, SCGB1D2, SCGB2A1, SCGB2B2, SCGB3A1,SCGN, SCIN, SCLT1, SCML1, SCN1B, SCN4A, SCNN1B, SCO1, SCOC, SCRN3,SCRT2, SCXA, SDAD1, SDAD1P1, SDAD1P2, SDAD1P4, SDCBP, SDCCAG3P1,SDCCAG3P2, SDE2, SDF2L1, SDHB, SDHD, SDIM1, SDR16C5, SDR42E1, SDS, SDSL,SEC11C, SEC14L3, SEC16B, SEC22A, SEC22B, SEC23A, SEC23B, SEC23IP,SEC24A, SEC24D, SEC31A, SEC61G, SEC62, SEC62-AS1, SEC63, SEC63P1,SECISBP2L, SECTM1, SEL1L, SEL1L2, SEL1L3, SELE, SELK, SELM, SELPLG,SEMA4A, SEMA4B, SEMA5A, SEMA6D, SEMG1, SENP3-EIF4A1, SENP8, SEPHS1P4,SEPHS1P6, SEPT10P1, SEPT2P1, SEPT7L, SEPT7P6, SEPT7P7, SEPT7P8, SEPW1,SERF2, SERINC1, SERINC3, SERP1, SERPINA3, SERPINA4, SERPINA5, SERPINB1,SERPINB2, SERPINB5, SERPINB6, SERPINB8, SERPINC1, SERPINE1, SERTAD1,SERTAD4, SERTAD4-AS1, SESN1, SETD3, SETD7, SETP18, SETP2, SETP20,SETP22, SETX, SF3A3P2, SF3B5, SFMBT1, SFR1, SFRP4, SFT2D2, SFTPA1,SFTPC, SFXN5, SGCA, SGCE, SGIP1, SGK1, SGK110, SGK3, SGMS1, SGMS2,SGOL1, SGOL1-AS1, SGPP1, SGPP2, SGSM1, SH2B3, SH2D2A, SH2D5, SH2D6,SH3BGR, SH3GL2, SH3GLB1, SH3YL1, SHCBP1, SHFM1, SHFM1P1, SHOC2, SHQ1,SHROOM1, SIAH2, SIAH3, SIDT1, SIGLEC1, SIGLEC10, SIGLEC11, SIGLEC14,SIGLEC16, SIGLEC5, SIGLEC8, SIGLEC9, SIK1, SIK2, SIKE1, SIPA1L2, SIRPB1,SIRT1, SIX1, SIX3, SIX3-AS1, SIX4, SIX6, SKA2, SKA2L, SKIV2L2, SKP1,SKP1P1, SKP2, SLA, SLA2, SLAIN2, SLAMF1, SLAMF7, SLAMF8, SLAMF9, SLBP,SLC10A4, SLC10A5, SLC10A7, SLC11A1, SLC12A8, SLC14A2, SLC16A4, SLC16A6,SLC16A9, SLC17A6, SLC18A2, SLC19A2, SLC1A1, SLC1A2, SLC1A4, SLC22A15,SLC22A2, SLC22A24, SLC22A9, SLC25A17, SLC25A1P5, SLC25A24, SLC25A30,SLC25A32, SLC25A34, SLC25A3P2, SLC25A40, SLC25A45, SLC25A46, SLC25A52,SLC25A53, SLC25A5P1, SLC25A5P7, SLC25A6P4, SLC25A6P5, SLC26A2, SLC26A3,SLC26A5, SLC27A2, SLC27A6, SLC28A2, SLC28A3, SLC2A10, SLC2A12, SLC2A13,SLC2A2, SLC2A5, SLC2A9, SLC30A2, SLC30A5, SLC30A8, SLC31A1, SLC31A1P1,SLC31A2, SLC33A1, SLC34A2, SLC35A5, SLC35D3, SLC35E1P1, SLC35G1,SLC35G2, SLC35G6, SLC36A4, SLC38A4, SLC39A12, SLC39A14, SLC39A4,SLC39A6, SLC39A8, SLC3A1, SLC3A2, SLC40A1, SLC41A1, SLC44A1, SLC45A2,SLC45A3, SLC46A3, SLC47A2, SLC4A10, SLC4A1AP, SLC4A4, SLC4A7, SLC52A3,SLC5A1, SLC5A3, SLC5A4, SLC5A5, SLC6A13, SLC6A14, SLC6A17, SLC6A20,SLC6A6, SLC7A1, SLC7A2, SLC7A5, SLC7A5P1, SLC8A1, SLC8A1-AS1, SLC9A7P1,SLC9A9, SLC9A9-AS2, SLC9B2, SLC9C1, SLC9C2, SLCO1A2, SLCO5A1, SLFN11,SLFN12, SLFN5, SLIRP, SLK, SLMAP, SLMO2, SLPI, SLU7, SLX1B, SMAD1,SMARCA5, SMARCE1P6, SMC3, SMC5, SMCHD1, SMEK2, SMG1P1, SMIM-2-IT1,SMNDC1, SMPDL3A, SNAI2, SNAP23, SNAP25, SNAP25- AS1, SNAP29, SNAP91,SNAPC1, SNAPC5, SNCA, SNCB, SNHG10, SNHG12, SNHG9, SNIP1, SNORA11,SNORA12, SNORA15, SNORA16, SNORA16B, SNORA22, SNORA24, SNORA25, SNORA26,SNORA27, SNORA28, SNORA2B, SNORA31, SNORA32, SNORA33, SNORA4, SNORA46,SNORA47, SNORA51, SNORA55, SNORA57, SNORA58, SNORA5A, SNORA5C, SNORA60,SNORA65, SNORA66, SNORA67, SNORA68, SNORA70, SNORA71A, SNORA71B,SNORA71C, SNORA72, SNORA73, SNORA73B, SNORA75, SNORA7B, SNORA81,SNORA84, SNORD100, SNORD11, SNORD111, SNORD112, SNORD113, SNORD113-1,SNORD113-3, SNORD113-4, SNORD114-1, SNORD114-10, SNORD114-12,SNORD114-13, SNORD114-17, SNORD114-18, SNORD114-21, SNORD114-25,SNORD114-26, SNORD114-27, SNORD114-28, SNORD114-3, SNORD114-4,SNORD114-5, SNORD114-6, SNORD114-7, SNORD115-12, SNORD115-21,SNORD115-44, SNORD115-45, SNORD116-12, SNORD116-13, SNORD116-16,SNORD116-29, SNORD116-4, SNORD116-8, SNORD12, SNORD127, SNORD12C,SNORD14A, SNORD14E, SNORD19, SNORD19B, SNORD1B, SNORD36C, SNORD37,SNORD3A, SNORD3B-1, SNORD3B-2, SNORD43, SNORD51, SNORD53_SNORD92,SNORD56, SNORD6, SNORD63, SNORD66, SNORD69, SNORD88, SNORD88A, snoU13,SNRNP27, SNRPE, SNRPEP2, SNRPEP4, SNRPF, SNRPFP1, SNRPGP10, SNRPGP14,SNRPGP2, SNRPGP4, SNTG1, SNW1, SNX10, SNX13, SNX14, SNX16, SNX18P13,SNX18P3, SNX18P9, SNX19P2, SNX2, SNX20, SNX25, SNX25P1, SNX29, SNX29P2,SNX3, SNX5, SNX5P1, SNX8, SOAT1, SOBP, SOCS1, SOCS2, SOCS2-AS1, SOCS3,SOCS4, SOCS5, SOD1, SOD2, SOD3, SOGA3, SOHLH2, SORL1, SORT1, SOS2,SOWAHA, SOWAHB, SOX18, SOX2-OT, SOX30, SOX6, SP1, SP100, SP110, SP140,SP140L, SPA17, SPAG1, SPAG6, SPARCL1, SPATA1, SPATA16, SPATA18, SPC24,SPC25, SPCS1, SPCS2, SPCS3, SPDYA, SPDYE6, SPDYE8P, SPEF1, SPEM1,SPESP1, SPHK1, SPI1, SPICE1, SPINK13, SPINK2, SPINK9, SPIRE1, SPOPL,SPP1, SPPL2A, SPR, SPRR1A, SPRR2A, SPRYD3, SPRYD7, SPSB1, SPTB, SPTLC1,SPTLC1P1, SPTLC1P4, SPTLC1P5, SPTSSA, SPTY2D1, SQRDL, SRBD1, SRD5A1,SRD5A1P1, SRGAP2, SRGAP2-AS1, SRGAP2B, SRGAP3-AS1, SRGAP3-AS2,SRGAP3-AS4, SRGN, SRP54, SRP68P1, SRP68P2, SRP72, SRPR, SRPRB, SRXN1,SSB, SSBP1, SSBP2, SSFA2, SSPN, SSR1, SSR3, SSSCA1, SSX2IP, SSXP10,ST13, ST13P13, ST13P14, ST14, ST20, ST3GAL5, ST3GAL6, ST3GAL6-AS1,ST7-AS2, ST7L, STAG2, STAMBPL1, STAP1, STAP2, STARD13-AS2, STARD3NL,STAT3, STAT4, STAT5A, STAT5B, STAU2, STAU2-AS1, STBD1, STEAP2, STEAP3,STEAP3-AS1, STEAP4, STIM2, STK3, STK38L, STK4, STK4-AS1, STOM, STPG2,STRAP, STRCP1, STT3A, STX11, STX12, STX17, STX19, STX1A, STXBP1, STXBP3,STXBP5, STXRP5- AS1, STXBP6, STYXL1, SUB1P1, SUB1P3, SUB1P4, SUCLA2-AS1,SUCLA2P3, SUCLG1, SUCLG2, SUCLG2P2, SUCO, SUDS3P1, SUGT1, SULT1A1,SULT1A2, SULT1A3, SULT6B1, SUMO1, SUMO2P3, SUMO2P4, SUMO3, SUMO4, SUN3,SURF2, SURF4, SUSD1, SUZ12, SVIP, SVOPL, SWAP70, SYBU, SYCE1, SYCE3,SYCN, SYCP2, SYCP3, SYF2, SYF2P2, SYK, SYNCRIP, SYNE2, SYNGR4, SYNM,SYNPO, SYPL1, SYT13, SYT14, SYT16, SYT4, SYT8, SYTL2, SYTL3, TAB2,TABS-AS1, TAB3-AS2, TACC1, TACSTD2, TADA1, TAF1, TAF12, TAF13, TAF1A,TAF1B, TAF1D, TAF4B, TAF5, TAF7, TAF7L, TAF9, TAF9B, TAF9BP1, TAF9P3,TAGAP, TAGLN2P1, TAL2, TANC1, TANC2, TAOK3, TAP1, TAPBP, TAPBPL, TARDBP,TARS, TAS1R1, TAS2R20, TAS2R3, TAS2R31, TAS2R38, TAS2R4, TAS2R64P, TAT,TATDN2P2, TATDN3, TAX1BP1, TBC1D12, TBC1D15, TBC1D22A, TBC1D23, TBC1D29,TBC1D2B, TBC1D30, TBC1D3B, TBC1D3H, TBC1D3P1-DHX40P1, TBC1D3P6, TBC1D4,TBC1D8, TBC1D8B, TBC1D9, TBCAP3, TBCCD1, TBK1, TBL1XR1, TBL1XR1- AS1,TBP, TBPL1, TBR1, TBX19, TBX21, TBXA2R, TC2N, TCEA1, TCEA1P2, TCEA1P4,TCEAL6, TCEANC, TCEB3B, TCERG1L, TCF15, TCF21, TCF4, TCHH, TCL1B, TCL6,TCN1, TCP1, TCP10L, TCP11, TCP11L2, TCP1P1, TCTE3, TCTEX1D1, TDGF1,TDGF1P4, TDGF1P6, TDP2, TDPX2, TDRD12, TDRD5, TDRD6, TDRD9, TDRG1,TEAD4, TEC, TEK, TEKT1, TEP1, TERF1P2, TESC, TEX10, TEX14, TEX19,TEX21P, TEX26-AS1, TEX29, TEX30, TEX35, TEX9, TFAM, TFB2M, TFCP2,TFCP2L1, TFEB, TFEC, TFP1, TFP1, TFRC, TG, TGDS, TGFA, TGFBR3, TGFBR3L,TGM2, TGM5, TGOLN2, THADA, THAP10, THAP5, THAP9, THAP9-AS1, THBD, THEM2,THEM6, THEMIS2, THNSL1, THNSL2, THOC7, THUMPD2, THUMPD3, TICAM2, TIFA,TIGD1, TIGD1L2, TIGD2, TIGD7, TIGIT, TIMM17A, TIMM23, TIMM8A, TIMMDC1,TIMP2, TIMP4, TINF2, TIPARP, TIPIN, TIPRL, TLK1, TLK1P1, TLK2P1, TLL1,TLL2, TLR1, TLR2, TLR3, TLR4, TLR6, TLR9, TM2D1, TM2D3, TM4SF1, TM4SF18,TM7SF3, TM9SF2, TM9SF3, TMA16P2, TMBIM6, TMC2, TMC5, TMCO1, TMCO2,TMCO4, TMCO5B, TMED10, TMED10P, TMED10P1, TMED11P, TMED2, TMED5, TMED6,TMED7, TMED7-TICAM2, TMEM100, TMEM106A, TMEM106A-AS1, TMEM106C, TMEM108,TMEM109, TMEM110, TMEM111, TMEM116, TMEM117, TMEM119, TMEM123, TMEM126A,TMEM126B, TMEM133, TMEM135, TMEM14B, TMEM14C, TMEM150C, TMEM154,TMEM156, TMEM158, TMEM161B, TMEM161B-AS1, TMEM163, TMEM165, TMEM167A,TMEM167B, TMEM168, TMEM17, TMEM173, TMEM194A, TMEM2, TMEM200A, TMEM208,TMEM209, TMEM211, TMEM212, TMEM219, TMEM236, TMEM241, TMEM246, TMEM26,TMEM27, TMEM30A, TMEM30B, TMEM33, TMEM38B, TMEM39A, TMEM40, TMEM41B,TMEM43, TMEM44- AS1, TMEM48, TMEM5, TMEM54, TMEM57, TMEM59, TMEM60,TMEM61, TMEM64, TMEM66, TMEM68, TMEM69, TMEM70, TMEM87A, TMEM8C,TMEM97P1, TMEM99, TMEM9B, TMF1, TMIE, TMLHE, TMOD1, TMOD2, TMOD4,TMPRSS11B, TMPRSS11F, TMPRSS12, TMPRSS15, TMPRSS2, TMPRSS4, TMSB10P1,TMSB4XP2, TMSB4XP4, TMSB4Y, TMX1, TMX2, TMX4, TncRNA, TNFAIP3, TNFAIP8,TNFAIP8L2, TNFRSF10C, TNFRSF11A, TNFRSF11B, TNFRSF12A, TNFRSF14,TNFRSF17, TNFRSF1B, TNFRSF21, TNFRSF4, TNFRSF8, TNFRSF9, TNFSF10,TNFSF11, TNFSF13, TNFSF13B, TNFSF14, TNFSF9, TNIK, TNKS2, TNN, TNNI2,TNRC18P1, TNS1, TNS3, TNS4, TOB2P1, TOMM22P4, TOMM22P5, TOMM7, TOMM70A,TOP1P1, TOPORS, TOR1AIP1, TP53RK, TPD52, TPH1, TPH2, TPI1P3, TPM3P8,TPP1, TPP2, TPPP3, TPRKB, TPRX1, TPT1, TPTE2P5, TPTE2P6, TPTEP1, TRAC,TRAF3IP2, TRAF3IP3, TRAF5, TRAK2, TRAM1, TRAM1L1, TRAPPC11, TRAPPC4,TRAPPC6B, TRAV27, TRAV30, TRDC, TREM1, TREM2, TREML1, TREML3P, TREX2,TRIAP1, TRIB1, TRIM23, TRIM25, TRIM29, TRIM34, TRIM37, TRIM38, TRIM4,TRIM47, TRIM48, TRIM54, TRIM60P17, TRIM63, TRIM7, TRIM72, TRIM9, TRIP10,TRIP11, TRIP12, TRIQK, TRMT10A, TRMT10C, TRMT11, TRMT12, TRMT1L, TRMT6,TRMT61B, TRNAI2, TRNT1, TROVE2, TRPC5OS, TRPM3, TRPM6, TRPM7, TRPM8,TRPS1, TRPV3, TRUB1, TSACC, TSC22D1, TSC22D3, TSEN15, TSFM, TSGA13,TSGA14, TSHB, TSHZ1, TSHZ2, TSHZ3, TSLP, TSN, TSPAN1, TSPAN12, TSPAN13,TSPAN2, TSPAN5, TSPAN7, TSPAN8, TSPEAR, TSPYL1, TSPYL2, TSPYL5, TSPYL6,TSSK1A, TSSK1B, TSTD2, TTBK2, TTC1, TTC13, TTC15, TTC17, TTC22, TTC27,TTC30A, TTC39B, TTC3P1, TTC4P1, TTC7B, TTF1, TTF2, TTI2, TTLL11-IT1,TTLL7-IT1, TTPA, TUBA1B, TUBA1C, TUBA3GP, TUBD1, TUBE1, TUFT1, TULP3P1,TWF1, TWIST1, TWISTNB, TWSG1, TXK, TXLNB, TXLNG, TXN, TXNDC11, TXNDC15,TXNDC2, TXNDC5, TXNDC9, TXNL1, TXNRD1, TYMS, TYRO3P, TYROBP, TYW1B,TYW3, U1, U2, U3, U4, U47924.19, U47924.27, U52111.12, U6, U6atac, U7,U73169.1, U8, U82695.10, UAP1, UBA2, UBA5, UBA7, UBAC2- AS1, UBASH3A,UBE2A, UBE2B, UBE2CP2, UBE2D3, UBE2D3P1, UBE2D3P2, UBE2D4, UBE2F,UBE2HP1, UBE2J1, UBE2L4, UBE2L5P, UBE2QL1, UBE2U, UBE2V1P1, UBE2V2,UBE3A, UBE3C, UBL3, UBL4B, UBLCP1, UBP1, UBQLN1, UBQLN2, UBR1, UBR3,UBR7, UBTFL6, UBXN2B, UBXN4, UBXN6, UBXN8, UCHL1, UCHL3, UCHL5, UCP1,UFL1, UFM1, UFSP1, UFSP2, UGDH, UGDH-AS1, UGGT2, UGP2, UGT2B15, UGT8,UHMK1, UHRF1BP1, UHRF1BP1L, ULBP1, ULBP2, ULK4, ULK4P2, UMODL1, UNC50,UNC5CL, UPF2, UPF3AP3, UPP2, UPRT, UQCRB, UQCRBP1, UQCRBP3, URI1, USE1,USMG5, USMG5P1, USO1, USP1, USP12, USP12PY, USP16, USP2, USP25, USP31,USP32P1, USP32P2, USP38, USP43, USP44, USP46, USP46-AS1, USP48, USP49,USP50, USP7, USP8, USP9X, USPL1, UTF1, UTP14C, UTP15, UTP18, UTP3, UTS2,VAMP1, VAMP2, VAMP4, VAMP5, VAMP8, VAPA, VAPB, VAT1L, Vault, VAV1, VAV3,VBP1, VCAM1, VCPIP1, VDAC1, VDAC1P1, VDAC1P2, VDAC1P6, VDAC3, VDR,VEGFA, VGF, VHLL, VIMP, VIP, VLDLR, VMA21, VMP1, VN1R104P, VN1R110P,VN1R14P, VN1R5, VN2R19P, VOPP1, VPREB3, VPS13C, VPS37A, VPS37C, VPS4A,VPS54, VRK2, VSIG10, VSX1, VTI1B, VTI1BP1, VTI1BP2, VTRNA1-1, VTRNA1-2,VERNA1-3, VWA3A, VWA3B, VWC2L, VWDE, VWF, WAC, WAPAL, WARS, WASF2,WASF4P, WASL, WBP1LP2, WBP2NL, WBP4, WBSCR22, WBSCR27, WDFY2, WDFY3-AS2, WDFY4, WDPCP, WDR12, WDR16, WDR3, WDR36, WDR38, WDR4, WDR41, WDR43,WDR44, WDR47, WDR49, WDR52-AS1, WDR53, WDR5B, WDR61, WDR67, WDR69,WDR76, WDR82P1, WDR89, WDYHV1, WEE2, WFDC10B, WFDC3, WFIKKN2, WHAMM,WHAMMP2, WHAMMP3, WI2- 1896O14.1, WI2-2373I1.1, WISP3, WLS, WNT10A,WNT16, WNT4, WNT7B, WNT9A, WSB2, WSCD2, WTAPP1, WWC1, WWC2-AS1,WWC3-AS1, WWP1, WWTR1-AS1, WWTR1-IT1, XAF1, XBP1, XBP1P1, XCR1, XDH, XG,XIAP-AS1, XIRP1, XIST, XKR9, XPA, XPO1, XPO4, XPOT, XPOTP1, XPR1, XRRA1,XXbac-B444P24.10, XXbac-B476C20.10, XXbac-B476C20.11, XXbac- B476C20.14,XXbac-B476C20.17, XXbac-BPG55C20.7, XX-C2158C12.2, XX- C2158C6.1,XX-C2158C6.3, XX-FW80269A6.1, XX-FW83128A1.2, XXyac- YX155B6.2,XXyac-YX65C7_A.2, XXYLT1-AS2, XYLB, Y_RNA, YARS, YBX1P1, YBX1P2, YBX1P3,YIPF4, YIPF5, YIPF6, YOD1, YRDCP2, YSK4, YTHDC2, YWHAH, YWHAQ, YWHAQP6,YWHAZP5, YY2, Z69666.2, Z73979.1, Z83001.1, Z84721.4, Z95704.3,Z98881.1, ZAN, ZAR1, ZBP1, ZBTB1, ZBTB10, ZBTB20, ZBTB20-AS1,ZBTB20-AS3, ZBTB20-AS4, ZBTB24, ZBTB25, ZBTB38, ZBTB4, ZBTB40-IT1,ZBTB6, ZBTB7A, ZBTB8A, ZBTB8OSP1, ZC3H12C, ZC3H15, ZC3H6, ZC3HAV1,ZCCHC14, ZCCHC2, ZCCHC7, ZCCHC9, ZCRB1, ZCWPW2, ZDHHC19, ZDHHC2,ZDHHC20-IT1, ZDHHC20P4, ZEB1, ZEB1-AS1, ZEB2, ZFAND1, ZFAND5, ZFC3H1,ZFP1, ZFP106, ZFP14, ZFP2, ZFP3, ZFP62, ZFP82, ZFP91, ZFYVE28, ZFYVE9,ZFYVE9P1, ZHX1, ZIM3, ZMAT1, ZMAT3, ZMAT5, ZMPSTE24, ZMYM5, ZMYM6,ZMYND10, ZMYND11, ZMYND12, ZNF10, ZNF12, ZNF136, ZNF138, ZNF14, ZNF146,ZNF148, ZNF165, ZNF17, ZNF175, ZNF181, ZNF182, ZNF189, ZNE19, ZNF197-AS1, ZNF22, ZNF221, ZNF225, ZNF230, ZNF234, ZNF239, ZNF24, ZNF248,ZNF25, ZNF252, ZNF252P, ZNF252P-AS1, ZNF256, ZNF257, ZNF263, ZNF271,ZNF275, ZNF280B, ZNF280D, ZNF281, ZNF283, ZNF285, ZNF295, ZNF295-AS1,ZNF300P1, ZNF302, ZNF322, ZNF322P1, ZNF323, ZNF331, ZNF33A, ZNF33AP1,ZNF343, ZNF347, ZNF350, ZNF354A, ZNF365, ZNF37A, ZNF385D, ZNF395,ZNF397, ZNF41, ZNF415, ZNF417, ZNF420, ZNF429, ZNF434, ZNF439, ZNF441,ZNF460, ZNF461, ZNF471, ZNF483, ZNF484, ZNF485, ZNF493, ZNF502,ZNF503-AS1, ZNF506, ZNF518B, ZNF519, ZNF525, ZNF540, ZNF546, ZNF547,ZNF556, ZNF558, ZNF559, ZNF563, ZNF564, ZNF567, ZNF569, ZNF57, ZNF570,ZNF571, ZNF572, ZNF583, ZNF585A, ZNF585B, ZNF594, ZNF595, ZNF596,ZNF600, ZNF616, ZNF619, ZNF625, ZNF630, ZNF638-IT1, ZNF639, ZNF643,ZNF652, ZNF658, ZNF658B, ZNF662, ZNF664, ZNF665, ZNF670, ZNF676, ZNF684,ZNF697, ZNF702P, ZNF705A, ZNF706, ZNF717, ZNF721, ZNF732, ZNF736,ZNF750, ZNF763, ZNF766, ZNF770, ZNF774, ZNF782, ZNF79, ZNF791, ZNF799,ZNF80, ZNF800, ZNF806, ZNF816, ZNF823, ZNF826P, ZNF829, ZNF831, ZNF835,ZNF839P1, ZNF84, ZNF841, ZNF844, ZNF845, ZNF850, ZNF859P, ZNF860,ZNF876P, ZNF878, ZNF890P, ZNF91, ZNF98, ZNFX1, ZNHIT6, ZNRF2, ZNRF3-AS1,ZNRF3-IT1, ZP4, ZPLD1, ZRSR1, ZSCAN10, ZSCAN12P1, ZSWIM5P2, ZUFSP, ZW10,ZXDA, ZXDB, ZYG11B, ZZEF1, ZZZ3

It is to be understood that the levels of expression of one or more ofthe genes listed in Table 2 are depicted in FIG. 5C as a fold change inexpression of in vitro-differentiated insulin-positive β-like cellscompared to mature β-cells.

It should also be appreciated that any gene listed in Table 2 can beused as a marker for detecting mature β-cells by measuring the level ofexpression of the gene in a cell, culture, cell line, tissue, orpopulation of cells (e.g., suspected of being β-cells), wherein if thelevel of expression of the gene in the cell, culture, cell line, tissue,or population of cells is elevated (for example, as depicted in FIG.5C), the cell, culture, cell line, tissue, or population of cellscomprises mature β-cells.

Those skilled in the art will also appreciate that any two or more ofthe genes listed in Table 2 can be used in combinations of up to N genes(where N is a positive integer greater than or equal to 2) as markersfor detecting mature β-cells by measuring the levels of expression ofthe combination of genes in a cell, culture, cell line, tissue, orpopulation of cells (e.g., suspected of being β-cells), wherein if thelevels of expression of the combination of genes in the cell, culture,cell line, tissue, or population of cells is elevated (for example, asdepicted in FIG. 5C), the cell, culture, cell line, tissue, orpopulation of cells comprises mature β-cells.

In some aspects, a marker of β-cell functional immaturity includes one,any combination or sub-combination, or all genes which are have a higherexpression level in fetal β-cells or in vitro-differentiatedinsulin-positive β-like cells compared to mature β-cells.

Exemplary genes which are differentially expressed in mature β-cellscompared to in vitro-differentiated insulin-positive β-like cells arelisted in Table 2C.

TABLE 2C Genes differentially expressed between mature β-cells comparedto in vitro-differentiated insulin-positive β-like cells A1CF, ABHD5,ABHD9, ACACB, ACBD7, ACCN2, ACCN4, ACOT7, ACOX2, ADAMTS9, ADAMTSL2,ADAP2, ADH1A, ADORA2A, ADSL, AEBP1, AFP, AGPAT9, AGR2, AMBP, ANGPTL2,ANKRD43, ANKS1B, ANKS4B, ANO6, ANO9, ANTXR2, AOX1, APC2, APCDD1L, APOA1,APOB, APOC1, APOC3, APOE, APOH, AQP10, ARHGAP24, ARHGAP4, ARHGEF3,ARID3B, ARID5B, ARL3, ARL9, ARX, ASAP2, ASAP3, ASB9, ASGR1, ATCAY,ATP6V1E2, AUTS2, B2M, B3GAT1, BAG3, BAMB1, BARD1, BASP1, BCAR3, BMP5,BPIL2, BTBD17, BTG3, C10orf10, C10orf140, C12orf27, C13orf15, C15orf57,C15orf59, C16orf59, C1orf127, C1orf133, C1orf158, C1QTNF5, C21orf119,C21orf63, C2CD4B, C2orf32, C2orf70, C3orf21, C3orf32, C3orf57, C5,C5orf13, C5orf38, C5orf4, C5orf53, C6orf115, C6orf117, C6orf89, C7orf23,C7orf52, CBA, C8orf44, C8orf47, C9orf123, C9orf66, C9orf9, C9orf95,CABLES1, CABP7, CADM4, CALB2, CAPN13, CARD10, CASR, CBX7, CCBP2,CCDC109B, CCDC110, CCDC74B, CCND3, CCPG1, CD14, CD44, CD5, CD55, CDC20,CDH10, CDH12, CDH22, CDH4, CDK6, CDKN1A, CDKN3, CDO1, CDS1, CEACAM1,CEBPA, CEBPD, CENPV, CENTA1, CFLAR, CGN, CGNL1, CHGB, CHKA, CHPF, CHST1,CHST13, C1B1, CLDN1, CLDN11, CLDN6, CLRN3, CNN3, CNRIP1, CNTNAP2,COL4A5, COX7A1, CPT1C, CPVL, CPXM1, CRABP1, CRH, CRYBA2, CSRP2, CTGF,CTNNBIP1, CTSF, CTXN1, CYB5R2, CYBA, CYP2J2, CYP2U1, CYR61, CYTH2,CYYR1, DACH2, DACT3, DBC1, DBN1, DCHS1, DCX, DDC, DDEF2, DENND2D, DGCR5,DHCR24, DKK3, DKK4, DLG2, DLK1, DLL3, DNAJC12, DNAJC15, DNM3, DOCK10,DOCK6, DOCK8, DPEP1, DPP4, DRAM1, DSC2, DSCR6, DUSP6, DYNC1I1, EDG4,EFEMP2, EFHD1, EFNB2, EGR1, EHBP1L1, EIF2B3, ELA3A, ELAVL3, ELF4, ELFN2,ELMO1, ELOVL2, EMID1, ENC1, ENPP2, ENPP5, ENTPD3, EPAS1, EPDR1, ERBB3,ERO1LB, EXOC7, F10, FABP7, FAM102A, FAM105A, FAM107A, FAM110B, FAM125B,FAM159B, FAM176B, FAM181B, FAM18A, FAM46B, FAM50B, FAT3, FEV, FGB,FGFR3, FGFR4, FHOD3, FICD, FKBP10, FKBP1B, FKBP5, FLJ14712, FLJ23834,FLJ25404, FLJ31568, FLJ41603, FLJ43752, FLNC, FNDC3B, FOXA1, FRMD4A,FSCN1, FSTL5, FXYD2, FXYD5, FXYD6, FZD2, G6PC2, GAL3ST1, GALK1, GALNT14,GALNTL1, GAS2, GAS2L3, GATA4, GBP2, GC, GCGR, GDPD5, GEM, GFRA3, GGH,GHDC, GHR, GHRL, GJA1, GLDC, GLIS3, GLT25D2, GLT8D2, GLTPD2, GLYCTK,GNG3, GOLSYN, GPBAR1, GPC2, GPC3, GPC4, GPER, GPM6A, GPR112, GPR137C,GPR37, GPR64, GPX7, GSN, GSTM1, GSTM2, GUCA2B, GUCY1A3, H3F3B, HABP2,HABP4, HADH, HAPLN4, HBQ1, HECA, HECW2, HES6, HHATL, HHEX, HIC2,HIST1H2BK, HIST1H4K, HIST2H2AA3, HIST2H2AA4, HIST2H2AC, HLA-A29.1,HLA-B, HLA-F, HLXB9, HMGCS1, HMGCS2, HMP19, HN1, HNF4G, HOPX, HS3ST4,HSF4, HSPA1A, HSPA2, HSPA4L, HSPA6, IAH1, IAPP, ICAM2, IER3, IER5,IFI35, IFIT1, IGDCC3, IGF2BP2, IGF2BP3, IGFBP2, IGFBP4, IGFBP5, IGSF9,IL11RA, IL13RA1, IL17RB, IL20RA, IMPA2, IQGAP2, IRX2, ISG20, ISX, ITIH4,ITM2A, ITPR3, KANK1, KCNG3, KCNK1, KCNK3, KCNT2, KCTD12, KIAA0247,KIAA0319, KIAA0363, KIAA0367, KIAA0408, KIAA0514, KIAA0672, KIAA1644,KIAA1683, KIAA1688, KIF12, KLF9, KLHDC8A, KLHDC8B, KLKB1, KRT19, LAMB1,LAMB2, LARGE, LASS1, LDHA, LDLRAP1, LIMCH1, LIN28B, LINGO1, LINGO4,LLGL1, LMO4, LOC100129913, LOC100130154, LOC100132117, LOC100133999,LOC100134134, LOC100134265, LOC100144604, LOC133993, LOC154761,LOC388494, LOC389332, LOC389493, LOC390705, LOC399744, LOC399959,LOC401720, LOC441066, LOC643740, LOC643911, LOC644390, LOC644670,LOC645233, LOC645566, LOC647251, LOC647307, LOC647886, LOC649841,LOC650200, LOC728431, LOC729137, LOC729314, LOC729970, LOXL3, LPAR1,LPAR2, LPHN2, LPPR5, LRCH2, LRRC56, LRRN2, LY6H, LY96, LZTS1, M6PRBP1,MAFA, MAMDC2, MAMLD1, MAN1C1, MAP3K6, MAPK12, MAPK15, 3-Mar, MARCKSL1,MATN2, ME3, MEG3, MEP1A, MET, METTL7A, MFAP4, MFGE8, MFNG, MGAT3,MGAT4A, MGAT4C, MGC16291, MGC16384, MGC18216, MGC39900, MIAT, MMP7,MNX1, MR1, MRAP2, MSL3L1, MT1X, MTE, MUC13, MVP, MX1, MYL5, MYLIP,MYO10, MYO16, MYO1D, MYOM1, NAP1L5, NBPF8, NDRG2, NDUFAE2, NETO2,NEURL1B, NFIA, NFIX, NIPSNAP1, NKD2, NKX6-1, NLF2, NLGN4X, NMNAT2,NOS1AP, NPEPL1, NPHS1, NPTX2, NPY, NQO2, NR0B1, NR2F1, NR3C2, NSMCE1,NYNRIN, OLFM1, ONECUT2, OSBP2, OVGP1, OXCT2, OXGR1, PABPC1L, PAFAH1B3,PALM2, PARM1, PAX4, PAX9, PBX2, PCDHB2, PCSK1, PCSK2, PDE8B, PDK4,PDLIM7, PDX1, PDZD3, PDZD8, PDZK1, PDZK1P1, PEG3, PENK, PFKFB2, PGM5,PHGDH, PHLDA3, PHYHIPL, PIR, PLA2G1B, PLA2G4C, PLCH2, PLCL2, PLCXD3,PLEKHA9, PLEKHB1, PLS3, PLTP, PLXDC2, PLXNA1, PLXNB1, PNCK, PNLIPRP2,PNMA3, PNMT, PON3, PPAP2B, PPM1E, PPP2R2C, PPP2R3B, PRAGMIN, PRAMEF19,PRICKLE1, PRKCH, PRKD1, PRNP, PROC, PRODH2, PROM1, PROX1, PRPH, PRR15L,PRSS1, PRSS23, PRSS8, PRUNE2, PSMB8, PTGR1, PTGS2, PTPN3, PTPRD, PTPRT,PURA, PXDN, QPRT, RAB11FIP5, RAB31, RAB34, RAPH1, RASD1, RASGRP1, RBBP8,RBP4, RBPMS2, RCOR2, RDH12, RENBP, RGL1, RGMA, RGS9, RHBDF1, RHOC, RHOU,RICH2, RIN2, RNASEL, RND3, RNF144, RNF144A, RNF165, ROR2, RORC, RPRM,RPS19BP1, RYR1, S100A10, S100A16, S100A4, SCARA3, SCD5, SCGB2A1, SCIN,SDF2L1, SELENBP1, SELM, SEMA3A, SEMA6C, 9-Sep, SERP1, SERPINA1,SERPINA10, SERPINF1, SERPINF2, SERTAD4, SFRP1, SGMS2, SH3GL2, SHC3,SHISA2, SIRPA, SIX4, SLC12A5, SLC16A9, SLC17A6, SLC17A8, SLC17A9,SLC1A4, SLC25A34, SLC27A3, SLC30A8, SLC35D3, SLC38A1, SLC39A5, SLC44A3,SLC45A3, SLCO2A1, SMYD3, SNCAIP, SNHG9, SNORA12, SNORD114-3, SNX26,SOCS2, SORBS1, SORL1, SOX11, SPATA18, SPATS2L, SPIRE1, SPON2, SRRM4,SRXN1, SSPO, ST6GAL1, ST6GALNAC5, STC2, STEAP2, STMN1, STMN4, STOM,STRA6, SURF4, SVIL, SYK, SYNGR4, SYT13, TAP1, TCF3, TGEBR2, TGEBR3,TGIF2, TGOLN2, TH, THBS3, TICAM2, TIMP2, TLE6, TM7SF2, TMEM109, TMEM163,TMEM190, TMEM27, TMEM56, TMEM61, TMEM86B, TMEM98, TMSB15A, TNFRSF21,TNFRSF25, TOX3, TP53I3, TP53INP1, TPST2, TRIM24, TRIM4, TRIM46, TRIOBP,TRIP6, TRO, TSHZ3, TSPAN14, TSPAN6, TSPYL5, TST, TTLL10, UCP2, UNC5A,UNC5CL, VANGL2, VASN, VAV3, VCAN, VGF, VIL1, VIM, VSTM2, VSTM2L, VTN,VWCE, WDR86, WEE1, WNT4, WSCD2, XBP1, XKR4, ZBTB20, ZDHHC8P, ZFP3,ZFPM1, ZFR2, ZNF217, ZNF331, ZNF385D, ZNF439, ZNF532, ZNF618

It should be appreciated that any gene listed in Table 2C can be used asa marker for distinguishing between mature β-cells and immature β-cellsby measuring the level of expression of the gene in a cell, culture,cell line, tissue, or population of cells (e.g., suspected of beingβ-cells), wherein if the level of expression of the gene in the cell,culture, cell line, tissue, or population of cells is similar to thelevel of expression in mature β-cells then the cell, culture, cell line,tissue, or population of cells comprises mature β-cells, and wherein ifthe level of expression of the gene in the cell, culture, cell line,tissue, or population of cells is similar to the level of expression inin vitro-differentiated β-cells, then the cell, culture, cell line,tissue, or population of cells comprises immature β-cells.

Those skilled in the art will also appreciate that any two or more ofthe genes listed in Table 2C can be used in combinations of up to Ngenes (where N is a positive integer greater than or equal to 2) asmarkers for distinguishing mature β-cells from immature β-cells bymeasuring the levels of expression of the combination of genes in acell, culture, cell line, tissue, or population of cells (e.g.,suspected of being β-cells), wherein if the levels of expression of thecombination of genes in the cell, culture, cell line, tissue, orpopulation of cells are similar to the levels of expression of the samecombination of genes in mature β-cells then the cell, culture, cellline, tissue, or population of cells comprises mature β-cells, andwherein if the levels of expression of the combination of genes in thecell, culture, cell line, tissue, or population of cells are similar tothe levels of expression of the same combination of genes in invitro-differentiated insulin-positive β-like cells then the cell,culture, cell line, tissue, or population of cells comprises immatureβ-cells

In some aspects, a marker of β-cell functional immaturity includes one,any combination or sub-combination, or all genes which are have a higherexpression level in fetal β-cells or in vitro-differentiatedinsulin-positive β-like cells compared to mature β-cells.

In some embodiments of this and other aspects of the invention, geneswhich have a higher expression level in fetal β-cells compared to matureβ-cells are listed in Table 3 (Table 3 includes both Tables 3A and 3B)

TABLE 3A Genes having higher expression levels in fetal β-cells comparedto mature β-cells SOX4, LZTR1, CSRNP3, HHEX, PROX1, RFX1, SOX8, ZNF423,LHX4, SOX11, ISX, NFIB, PAX4, LMO4, NOTCH1, ASCL2, TCF3, RCOR2, EGR1,FOS, MYCN, EVI1, LZTS1, GHRL, PYY, HNF1A, INSM1, IRX2, ISL1, MYT1,NEUROG3, ACSS1, GCK, HCN3, KCNJ4, COL1A1, FFAR1

TABLE 3B Genes having higher expression levels in fetal β-cells comparedto mature β-cells A1CF, AACS, AADAT, ABAT, ABCC10, ABCC5, ABHD9, ABP1,ACACA, ACAP3, ACBD7, ACCN1, ACCS, ACP2, ACVR1C, ADPRHL2, ADRA2A, ADSL,AGAP6, AGAP8, AGBL4, AGPAT4, AGRN, AHCY, AKT1, ALDH7A1, ALMS1, ALPP,AMACR, AMT, ANKDD1A, ANKRD30B, ANKRD36B, ANKRD50, ANKS1B, ANO6, ANTXR2,ANXA4, AOF2, AP1M2, AP2A2, APEX1, ARC, ARF5, ARGLU1, ARHGEF19, ARHGEF4,ARID3A, ARID3B, ARIH2, ARL3, ARRDC1, ARVCF, ASAP3, ASB9, ASCL2, ASGR1,ASS1, ATG16L2, ATG2A, ATP2B4, ATP6V1B1, ATXN2L, ATXN7L2, AUTS2, AXIN2,B4GALNT4, B4GALT5, BACE1, BAMBI, BASP1, BAT2L, BAZ2B, BCL11A, BCS1L,BEND5, BIK, BLZF1, BMS1P5, BOP1, BPHL, BRD3, BRF1, BRSK2, BTBD17,BZRAP1, C10orf114, C10orf140, C10orf33, C10orf35, C11orf41, C11orf61,C12orf27, C12orf51, C12orf76, C14orf102, C14orf139, C14orf159, C14orf79,C14orf85, C15orf63, C16orf59, C16orf62, C16orf7, C16orf93, C17orf76,C18orf45, C1orf53, C1orf59, C1orf93, C1QTNF4, C1QTNF6, C20orf12,C21orf29, C21orf45, C21orf54, C21orf56, C22orf29, C2orf54, C2orf68,C3orf21, C3orf50, C3orf59, C5orf13, C6orf124, C6orf134, C6orf192,C6orf26, C6orf59, C7orf38, C8ORFK32, C9orf117, C9orf167, C9orf45,C9orf66, C9orf7, CABIN1, CABP7, CACNG4, CAD, CADM4, CALB2, CALCOCO1,CALHM2, CALY, CAMKV, CAPSL, CARD10, CARD8, CARD9, CASP2, CATSPER2, CBLB,CBLN2, CBX2, CCDC125, CCDC14, CCDC22, CCDC8, CCDC88B, CCDC88C, CCNF,CCNL1, CDAN1, CDC25B, CDH12, CDH3, CDK10, CDK5RAP3, CDK9, CDO1, CECR6,CELSR2, CELSR3, CENPV, CEP135, CEP164, CEP27, CEP78, CES2, CES8, CFLAR,CGNL1, CHD4, CHD7, CHD8, CHFR, CHGA, CHST12, CIDEB, CKAP2, CKB, CLASP1,CLIC6, CLIP3, CLPS, CLRN3, CNN3, CNNM3, CNOT6, CNTNAP2, CNTNAP4,COL16A1, COL18A1, COL1A2, COL3A1, COL4A5, COL5A1, COL5A2, COL6A1,COL8A2, COPG2IT1, COPS7B, CORO1B, COX19, CPT1C, CRABP1, CRMP1, CROCC,CRYBA2, CSF2RA, CSNK1E, CSNK1G2, CSRNP3, CTNNBIP1, CTPS, CTSK, CTXN1,CX3CL1, CXXC4, CYB5A, CYP2C8, CYP2J2, CYP2W1, CYTH2, DACT3, DAGLB, DARC,DBC1, DBN1, DCAF7, DCDC5, DCHS1, DCLRE1C, DCX, DDAH2, DDB1, DDC, DDX27,DECR2, DENND2A, DENR, DKEZp761P0423, DKK3, DLG5, DLK1, DMAP1, DMWD,DNAH1, DNALI1, DNHD2, DOCK6, DOCK8, DOK4, DOLPP1, DPEP1, DPYSL3, DRD1IP,DSCR6, DTX1, DUSP1, DUSP18, DUSP9, DUT, E2F5, EBF1, EBF4, ECEL1, EDG4,EFCAB4A, EFEMP2, EFNA4, EFNB1, EFNB2, EFS, EGR1, EHD1, EIF2AK4, EIF2C1,ELAVL3, ELFN2, ELMO2, EMID1, EML1, ENHO, EP400, EPC1, EPHA4, EPHB2,EPOR, ERGIC1, ERMAP, ETV3, EVI1, EVL, EVPL, EXD3, EXOC7, EXOSC10, EYA2,F10, FABP5, FABP5L2, FAM110B, FAM116B, FAM117B, FAM163A, FAM175A,FAM176B, FAM195B, FAM32A, FAM39E, FAM40A, FAM73A, FAM83E, FAM92B, FANCE,FARP1, FBXL10, FBXW9, FCGRT, FER1L5, FFAR1, FFAR3, FGD1, FGD3, FGFR3,FGFR4, FIT1, FKBP1P1, FKRP, FLJ10246, FLJ25363, FLJ30092, FLJ31568,FLJ35258, FLJ36131, FLJ39827, FLJ41649, FLJ42627, FLJ44124, FLJ46309,FLJ46906, FLJ90757, FLRT2, FMNL2, FNBP1L, FOS, FOXJ1, FOXO4, FOXP4,FRAS1, FRAT2, FSTL3, FTCD, FUT4, FXYD2, FXYD3, FXYD6, FYN, FZD3, FZD9,GABBR1, GAL3ST1, GALM, GALNS, GALNT3, GALNTL1, GAS2L3, GAS8, GATM, GATS,GGH, GGT7, GJB1, GJC2, GLB1L2, GLIPR2, GLYCTK, GNL3L, GNMT, GOLGA8A,GPBAR1, GPC1, GPC2, GPER, GPR114, GPR125, GPR137C, GPR42, GPR98, GPT,GPT2, GPX7, GRK4, GRK5, GRM4, GSTM1, GSTM2, GTF21P1, GUSBL1, GUSBL2,H19, H2AFY2, HCFC1, HCN3, HDAC6, HEXDC, HHATL, HHEX, HIATL2, HIC2,HIF3A, HIST1H4J, HIST1H4K, HN1, HNF1A, HNRNPA3, HNRNPH1, HNRNPR, HNRNPU,HNRPA1L-2, HNRPA1P4, HNRPH1, HPCA, HSBP1, HSD17B7, HSPC047, HSPC268,HTT, HYMAI, IDH2, IFFO2, IFT140, IGDCC3, IGDCC4, IGF2BP2, IGF2BP3,IGFALS, IGFBP5, IGSF9, IGSF9B, IL11RA, IMPA2, INPP5E, INSM1, INTS3,IP6K2, ISL1, ISX, ITM2A, ITPA, ITPRIP, JARID2, JMJD2B, KATNB1, KCND1,KCNH3, KCNH6, KCNH8, KCNJ4, KCNQ1OT1, KCNQ2, KCNT2, KDM5B, KIAA0114,KIAA0182, KIAA0427, KIAA0492, KIAA0773, KIAA0889, KIAA0892, KIAA0895L,KIAA0922, KIAA1217, KIAA1543, KIAA1545, KIAA1614, KIAA1688, KIAA1843,KIF12, KIF3C, KIFC2, KLHDC8B, KLHL28, KNDC1, KRT19, KRT80, KTELC1,LAMA1, LAMB1, LAMC1, LANCL2, LARGE, LARP4B, LARS2, LDLRAD3, LEPREL1,LFNG, LHX4, LIME1, LIMS2, LIN52, LINGO1, LINGO2, LLGL1, LLGL2, LMNB2,LMO3, LMO4, LOC100127975, LOC100128062, LOC100128098, LOC100128126,LOC100128288, LOC100128374, LOC100128510, LOC100128729, LOC100128974,LOC100129022, LOC100129211, LOC100129387, LOC100129441, LOC100129502,LOC100129580, LOC100129608, LOC100129905, LOC100129975, LOC100130053,LOC100130276, LOC100130353, LOC100130516, LOC100130835, LOC100131017,LOC100131541, LOC100131718, LOC100131786, LOC100132323, LOC100132347,LOC100132564, LOC100132585, LOC100132727, LOC100132740, LOC100132810,LOC100132901, LOC100133144, LOC100133516, LOC100133840, LOC100133999,LOC100134053, LOC100134134, LOC100134144, LOC100134159, LOC100134241,LOC100134265, LOC100134361, LOC100134584, LOC100134821, LOC100170939,LOC123688, LOC145837, LOC149134, LOC153561, LOC158301, LOC201725,LOC202781, LOC284167, LOC284297, LOC284422, LOC284757, LOC338758,LOC341230, LOC387934, LOC389168, LOC389765, LOC401098, LOC402112,LOC440157, LOC440345, LOC440704, LOC441268, LOC442041, LOC442582,LOC552889, LOC642031, LOC642741, LOC642852, LOC642909, LOC642956,LOC644935, LOC644979, LOC645233, LOC645452, LOC645566, LOC645648,LOC646044, LOC646897, LOC646996, LOC647251, LOC647691, LOC648024,LOC648057, LOC648059, LOC648526, LOC648852, LOC652002, LOC652377,LOC652900, LOC653157, LOC653210, LOC653352, LOC653629, LOC653829,LOC654103, LOC727877, LOC728105, LOC728153, LOC728411, LOC728448,LOC728452, LOC728457, LOC728485, LOC728499, LOC728519, LOC728565,LOC728608, LOC728640, LOC728643, LOC728661, LOC728779, LOC729120,LOC729351, LOC729559, LOC729978, LOC730173, LOC730993, LOC730995,LOC732360, LOC791120, LOC90113, LOC91461, LOC92497, LOXL1, LOXL3, LPAR2,LPHN1, LPHN2, LPPR5, LRAP, LRCH2, LRCH3, LRP1, LRPPRC, LRRC3, LRRC37B2,LRRC56, LRRC8A, LRRN2, LUC7L, LZTR1, LZTS1, MAFB, MAGT1, MAMDC4, MAOA,MAP3K12, MAP3K4, MAP4K2, MAPKAPK3, MARCKS, MARCKSL1, MARK3, MARVELD3,MAST1, MATN1, MBD4, MBD6, MCF2L, MED12, MED24, MED25, MEG3, MEG8, MEGF8,MEIS1, MEIS2, MEMO1, MEX3A, MEX3D, MFAP4, MFGE8, MFNG, MGAT3, MGC16121,MGC16384, MGC16703, MGC3032, MGC39900, MGC50722, MGC52000, MGC61598,MICAL1, MIR2116, MIR886, MKNK1, MLL, MLXIPL, MMP15, MMP23A, MMP23B,MOV10, MPL, MSI1, MSL3L1, MST1, MSTP9, MTF2, MTG1, MTHFD1L, MTHFR,MTMR4, MUM1, MXD4, MYB, MYBPC2, MYCN, MYH10, MYL7, MYO10, MYO5C, MYO7A,MYOM3, MYT1, MYT1L, N4BP1, N4BP2, N6AMT1, NARF, NASP, NAT11, NBPF8, NDN,NDST1, NDUFS2, NECAB3, NEK8, NETO2, NEURL, NEURL1B, NEURL4, NEUROD1,NFIB, NGFRAP1, NINL, NIPSNAP1, NISCH, NKTR, NLRP2, NNAT, NOTCH1, NPC1L1,NPEPL1, NPHS1, NPIP, NT5DC2, NTNG2, NUBPL, NUMBL, NUP62, NXN, NYNRIN,ODZ3, OSBP2, OTUB1, OVGP1, P2RY11, PABPC1L, PABPN1, PACSIN3, PAFAH1B3,PALM, PANK1, PAPSS1, PARD6G, PAX4, PBX2, PBX4, PCDH24, PCDHB19P, PCGF2,PCNT, PCYOX1L, PDCD4, PDE5A, PDGFD, PDGFRB, PDZD3, PEAR1, PEG3, PGAM2,PGD, PH-4, PHF16, PHLDB1, PIK3C2B, PIK3IP1, PIP5K2B, PIWIL4, PKDCC,PKN2, PLA2G4F, PLAGL1, PLAGL2, PLCG1, PLCH2, PLCXD1, PLDN, PLEKHA5,PLEKHA9, PLEKHB1, PLEKHF1, PLEKHG3, PLEKHH1, PLIN5, PLS3, PLSCR3,PLXNA1, PLXNA3, PLXNB1, PNMA3, PNMT, PODN, POLRMT, PPAPDC3, PPFIA4,PPFIBP1, PPOX, PPP1R13B, PPP1R14C, PPP1R16A, PPP1R9A, PPP4C, PRAGMIN,PRICKLE1, PRKCABP, PRKCDBP, PRKCG, PRKCQ, PRKCZ, PRKD1, PRO0628,PRO1853, PRODH, PRODH2, PROM1, ProSAPiP1, PROX1, PRR15L, PRR3, PRR5,PTBP2, PTCH1, PTK7, PTPRE, PTPRF, PTRH1, PXDN, PYCR1, QDPR, QPRT, QRFPR,R3HDM1, RAB11FIP3, RAB11FIP4, RAB25, RAB26, RAB36, RABL2B, RAGE, RANBP1,RAPGEF4, RAPGEF5, RASAL1, RASIP1, RASL11B, RASSF4, RAX2, RAXL1, RBM15B,RBM5, RBM6, RBM9, RBP1, RCC2, RCE1, RCN3, RCOR2, REC8, RELN, RFX1, RFX7,RGAG4, RGL3, RGMA, RHBDL2, RHOB, RIMBP2, RNF112, RNF165, RNF183, RNF31,RNF43, RNF44, RNU1A3, RNY1, RNY3, ROBO2, ROGDI, ROR2, RXRA, SAMD14,SAPS3, SARM1, SARS2, SBK1, SCARB1, SCIN, SCN9A, SCTR, SDC1, SDK2,SDR9C7, SEMA3A, SEMA4C, SEMA6A, SEMA6C, 2-Sep, 9-Sep, SERINC2, SERPINF2,SETDB1, SFRS14, SFRS8, SGPL1, SH3BP5L, SHROOM3, SLC12A9, SLC16A9,SLC22A16, SLC25A14, SLC25A27, SLC26A4, SLC27A3, SLC29A1, SLC2A8,SLC35E1, SLC38A1, SLC39A10, SLC44A3, SLC4A8, SLC5A8, SLIT2, SMA4,SMARCC1, SMARCD2, SMCR5, SMO, SNAPC4, SNORA28, SNORA6, SNORA67, SNORA80,SNORD36C, SNORD56, SNRNP70, SNX26, SOX11, SOX12, SOX4, SOX8, SPINK1,SPIRE2, SPNS2, SPOCK2, SPON1, SRPX, SSBP3, SSTR2, ST6GAL1, ST6GALNAC5,STAG3L2, STAG3L3, STK36, STMN1, STMN2, STRA6, SULF1, SV2B, SVIL,SYNJ2BP, TACC3, TAF15, TARBP1, TBC1D14, TBC1D24, TBC1D3I, TBC1D4, TBCB,TCEAL7, TCF1, TCF20, TCF3, TCF4, TCN2, TDG, TDRD1, TECPR1, TEKT2, TESC,TET1, TGFB3, TH, THBS3, THOC1, TIA1, TIAF1, TIMM22, TJP2, TLE2, TLE4,TLK2, TM6SF1, TMEFF2, TMEM106A, TMEM132A, TMEM132B, TMEM134, TMEM137,TMEM169, TMEM190, TMEM196, TMEM206, TMEM5, TMEM53, TMEM91, TMEM98,TMPRSS6, TMSB10, TMSB15A, TNFAIP8L1, TNFSF15, TOP1P2, TP53INP1, TRA2A,TRIM46, TRO, TRPM2, TRPM5, TRPM8, TSC2, TSC22D3, TSNAXIP1, TSPAN14,TSPAN17, TSPAN32, TSPAN33, TSPAN5, TSPAN6, TTC38, TTC5, TTLL3, TUBB1,TUBB2B, TUBB3, TUBB4, TYRO3, UBE2O, UBE2Q1, UCP2, UGT2B7, UNC13B, UNC5A,UPF3A, USH1C, USP49, VANGL2, VASH1, VASH2, VIL1, VPS37D, VPS8, VWCE,WDR48, WDR6, WDR74, WDR86, WIPI2, WNK2, WNT5B, WSB1, YPEL1, YRDC, ZBED4,ZBTB46, ZBTB47, ZBTB48, ZCCHC11, ZDHHC14, ZDHHC8P, ZFP90, ZFPM1,ZFYVE21, ZMIZ2, ZNF133, ZNF135, ZNF193, ZNF217, ZNF248, ZNF281, ZNF296,ZNF300, ZNF362, ZNF423, ZNF431, ZNF503, ZNF512B, ZNF518A, ZNF532,ZNF551, ZNF608, ZNF609, ZNF618, ZNF649, ZNF652, ZNF667, ZNF69, ZNF692,ZNF696, ZNF711, ZNF773, ZNF785, ZNF786, ZNF827, ZNF85, ZSWIM7

It is to be understood that the levels of expression of one or more ofthe genes listed in Table 3 are depicted in FIG. 6C as a fold change inexpression of mature β-cells compared to fetal β-cells.

It should also be appreciated that any gene listed in Table 3 can beused as a marker for detecting immature β-cells or fetal β-cells bymeasuring the level of expression of the gene in a cell, culture, cellline, tissue, or population of cells (e.g., suspected of being β-cells),wherein if the level of expression of the gene in the cell, culture,cell line, tissue, or population of cells is elevated (for example, asdepicted in FIG. 6C), the cell, culture, cell line, tissue, orpopulation of cells comprises immature β-cells or fetal β-cells.

Those skilled in the art will also appreciate that any two or more ofthe genes listed in Table 3 can be used in combinations of up to N genes(where N is a positive integer greater than or equal to 2) as markersfor detecting immature β-cells or fetal β-cells by measuring the levelsof expression of the combination of genes in a cell, culture, cell line,tissue, or population of cells (e.g., suspected of being β-cells),wherein if the levels of expression of the combination of genes in thecell, culture, cell line, tissue, or population of cells is elevated(for example, as depicted in FIG. 6C), the cell, culture, cell line,tissue, or population of cells comprises mature β-cells.

In some embodiments of this and other aspects of the invention, geneshaving higher expression levels in in vitro-differentiatedinsulin-positive β-like cells compared to mature β-cells are listed inTable 4 (Table 4 includes both Table 4A and Table 4B).

TABLE 4A Genes having higher expression levels in vitro-differentiatedinsulin- positive β-like cells compared to mature β-cells ZNF217, ISX,PBX2, HNF4G, ELF4, CEBPA, RCOR2, MSL3L1, EGR1, TCF3, LZTS1, TGIF2, HES6,AEBP1, LMO4, SOX11, IRX2, FEV, NR2F1, CHGA, GAST, GCG, GHRL, NTS, PYY,ARX, FOXA1, FOXA3, GATA4, IRX2, ISL1, NOTCH1, ONECUT2, PAX4, PROX1,SOX4, ACOX2, RIMS3, SLC2A1, SLC2A3, CACNA1E, HCN3, KCNB1, KCNJ2, DLL3,DPP4, HHEX, FOXA1

TABLE 4B Genes having higher expression levels in vitro-differentiatedinsulin- positive β-like cells compared to mature β-cells 7SK, A1CF,A2M-AS1, A2ML1-AS2, A2MP1, A3GALT2P, A4GALT, AAA1, AACS, AACSP1, AAMP,AASS, AB015752.4, ABC7-42389800N19.1, ABCA11P, ABCA12, ABCA4, ABCA7,ABCB10, ABCC1, ABCC10, ABCC4, ABCC6, ABCC6P1, ABCC6P2, ABCD1, ABCD4,ABCG4, ABCG5, ABHD11, ABHD11- AS2, ABHD12B, ABHD14A, ABHD14A-ACY1,ABHD15, ABHD9, ABL1, ABLIM2, ABLIM3, ABO, ABT1P1, ABTB1, ABTB2,AC000032.2, AC000078.5, AC000120.7, AC002066.1, AC002116.7, AC002310.17,AC002310.7, AC002365.1, AC002398.5, AC002472.11, AC002472.13,AC002477.1, AC002480.3, AC002480.5, AC002539.1, AC003090.1, AC003102.3,AC003664.1, AC003988.1, AC004053.1, AC004057.1, AC004152.5, AC004158.2,AC004158.3, AC004160.4, AC004166.7, AC004221.2, AC004231.2, AC004381.6,AC004386.4, AC004448.5, AC004449.6, AC004475.1, AC004538.3, AC004540.5,AC004543.2, AC004593.2, AC004623.2, AC004799.3, AC004837.4, AC004840.9,AC004862.6, AC004893.10, AC004893.11, AC004895.4, AC004906.3,AC004947.2, AC004957.5, AC004967.11, AC004967.7, AC004980.10,AC004980.7, AC004980.9, AC004985.12, AC004987.8, AC004987.9, AC005000.1,AC005003.1, AC005009.1, AC005009.2, AC005013.5, AC005019.3, AC005029.1,AC005034.3, AC005042.4, AC005071.1, AC005086.4, AC005154.5, AC005154.8,AC005204.2, AC005215.1, AC005256.1, AC005262.3, AC005300.5, AC005306.3,AC005324.6, AC005324.8-001, AC005326.2, AC005329.1, AC005329.7,AC005330.2, AC005391.3, AC005488.11, AC005513.1, AC005519.4, AC005534.6,AC005540.3, AC005562.2, AC005592.1, AC005592.3, AC005609.1, AC005625.1,AC005682.5, AC005682.6, AC005702.3, AC005702.4, AC005754.1, AC005757.6,AC005775.2, AC005841.1, AC005943.4, AC005943.5, AC005944.2, AC005971.3,AC006000.5, AC006003.3, AC006014.8, AC006023.8, AC006028.10, AC006042.7,AC006111.1, AC006116.1, AC006116.20, AC006132.1, AC006156.1, AC006160.5,AC006370.2, AC006372.1, AC006372.4, AC006372.5, AC006445.7, AC006465.4,AC006509.6, AC006547.14, AC006547.8, AC006946.15, AC007000.10,AC007000.12, AC007256.5, AC007285.7, AC007308.6, AC007383.3, AC007387.2,AC007391.2, AC007395.4, AC007401.1, AC007403.3, AC007464.1, AC007551.2,AC007557.1, AC007557.3, AC007563.3, AC007563.4, AC007563.5, AC007875.2,AC007881.4, AC007969.4, AC008063.2, AC008073.7, AC008073.9, AC008088.4,AC008103.5, AC008278.3, AC008440.10, AC008674.1, AC008676.1, AC008687.1,AC008697.1, AC008746.3, AC008993.2, AC008993.5, AC009065.1, AC009110.1,AC009120.5, AC009133.12, AC009133.15, AC009133.20, AC009227.2,AC009264.1, AC009336.24, AC009480.3, AC009492.1, AC009505.2, AC009542.2,AC009945.4, AC009955.8, AC009963.5, AC009965.2, AC010095.7, AC010127.3,AC010132.11, AC010148.1, AC010325.1, AC010336.1, AC010492.2, AC010492.4,AC010507.5, AC010525.6, AC010536.2, AC010615.1, AC010620.1, AC010649.1,AC010677.5, AC010729.1, AC010731.2, AC010746.4, AC010761.10,AC010761.13, AC010761.9, AC010894.3, AC010894.4, AC010904.1, AC010976.2,AC010982.2, AC010997.1, AC011290.4, AC011306.2, AC011343.1, AC011385.2,AC011443.1, AC011450.1, AC011475.1, AC011484.1, AC011491.1, AC011497.1,AC011551.1, AC011558.5, AC011718.1, AC011742.3, AC011899.9, AC012123.1,AC012358.4, AC012358.7, AC012363.7, AC012368.1, AC012445.1, AC012485.2,AC012499.1, AC012506.4, AC012668.2, AC013283.1, AC013400.2, AC013402.2,AC013439.4, AC013460.1, AC013472.3, AC013472.4, AC015691.13, AC015815.2,AC015815.6, AC015818.11, AC015818.6, AC015842.1, AC015849.2, AC015884.1,AC016405.1, AC016670.1, AC016683.5, AC016700.5, AC016708.2, AC016712.2,AC016716.2, AC016722.1, AC016722.2, AC016723.4, AC016725.4, AC016757.3,AC016773.1, AC016894.1, AC017116.8, AC018359.1, AC018638.1, AC018648.5,AC018693.6, AC018705.5, AC018737.6, AC018738.2, AC018799.1, AC018804.1,AC018804.6, AC018865.5, AC018865.8, AC018865.9, AC018892.9, AC019068.2,AC019070.1, AC019100.3, AC019118.2, AC019185.4, AC019205.1, AC020550.7,AC020743.3, AC020907.3, AC020915.1, AC021860.1, AC022007.4, AC022007.5,AC022182.1, AC022182.2, AC022210.2, AC022400.1, AC022498.1, AC022532.1,AC022819.2, AC023480.1, AC023490.1, AC023490.2, AC023590.1, AC024162.2,AC024475.1, AC024580.1, AC024896.1, AC024937.2, AC024937.4, AC024937.6,AC024940.1, AC025165.1, AC025165.8, AC025171.1, AC026956.1, AC027119.1,AC027307.1, AC027601.1, AC027612.1, AC037445.1, AC048382.4, AC051649.6,AC055764.1, AC055811.5, AC060834.2, AC060834.3, AC061961.2, AC061975.1,AC061992.2, AC062016.1, AC063976.7, AC064836.3, AC064852.5, AC066593.1,AC068014.1, AC068020.1, AC068129.2, AC068134.10, AC068137.1, AC068499.6,AC068522.4, AC068535.3, AC068580.6, AC068587.2, AC068641.1, AC068718.1,AC068831.10, AC068831.3, AC068831.6, AC069277.2, AC069278.4, AC069294.1,AC069513.4, AC072052.7, AC073052.1, AC073130.3, AC073133.2, AC073236.3,AC073283.4, AC073342.12, AC073415.2, AC073850.6, AC073869.2,AC073869.20, AC073957.15, AC074019.2, AC074212.5, AC074212.6,AC074289.1, AC074363.1, AC074389.6, AC078842.3, AC078883.3, AC078941.1,AC078942.1, AC079233.1, AC079354.5, AC079586.1, AC079610.2, AC079753.1,AC079776.1, AC079776.3, AC079780.3, AC079781.5, AC079781.8, AC079790.2,AC079807.2, AC080091.1, AC080125.1, AC083855.4, AC083862.6, AC083949.1,AC084018.1, AC084117.3, AC084125.4, AC087289.1, AC087650.1, AC090103.1,AC090519.5, AC090559.1, AC090587.5, AC090602.2, AC090627.1, AC091038.1,AC091153.4, AC091633.3, AC091878.1, AC092106.1, AC092159.2, AC092171.1,AC092171.4, AC092291.1, AC092329.1, AC092338.5, AC092535.1, AC092535.3,AC092619.1, AC092620.3, AC092638.2, AC092641.2, AC092675.3, AC092798.1,AC092839.1, AC092839.4, AC092902.1, AC093106.5, AC093107.7, AC093159.1,AC093375.1, AC093415.3, AC093415.5, AC093609.1, AC093616.4, AC093627.10,AC093627.6, AC093668.3, AC093690.1, AC093724.2, AC093734.11,AC093734.13, AC093818.1, AC093838.4, AC093838.7, AC096574.5, AC096669.2,AC097374.2, AC097468.4, AC097499.2, AC097635.4, AC097721.1, AC098474.1,AC098784.2, AC098826.5, AC099489.1, AC099668.5, AC100830.3, AC100830.5,AC100852.2, AC103828.1, AC103965.1, AC104113.3, AC104131.1, AC104532.2,AC104532.4, AC104655.3, AC104809.3, AC105052.1, AC105339.1, AC106782.18,AC106782.20, AC106801.1, AC106869.2, AC107057.2, AC108025.2, AC108039.2,AC108142.1, AC108479.2, AC109333.10, AC109642.1, AC109828.1, AC110079.1,AC110373.1, AC110619.1, AC110619.2, AC110781.3, AC110781.5, AC110926.4,AC112211.2, AC112211.3, AC112229.1, AC114273.1, AC114730.11, AC114730.8,AC115618.1, AC116609.2, AC116614.1, AC117372.1, AC118138.2, AC123023.1,AC124057.5, AC125232.1, AC125238.2, AC125634.1, AC126365.4, AC127496.1,AC130888.1, AC131180.3, AC131180.4, AC131971.3, AC132186.1, AC132216.1,AC133633.1, AC133919.6, AC135048.13, AC136704.1, AC137723.5, AC137934.1,AC138035.2, AC138623.1, AC138649.1, AC139100.3, AC139530.1, AC139887.4,AC140061.2, AC140061.8, AC140542.2, AC141586.5, AC141928.1, AC142528.1,AC145124.1, AC147651.2, AC159540.2, AC226118.1, ACAA1, ACAP3, ACBD4,ACBD7, ACCN2, ACCN4, ACE, ACER1, ACHE, ACIN1, ACOT11, ACOT7, ACOX2,ACOX3, ACP2, ACPT, ACR, ACSF2, ACSS3, ACTG1P1, ACTL6B, ACTL7B, ACTN3,ACTN4P2, ACTR1A, ACTR1B, ACTR3P2, ACVR1C, ACVR2A, ACVR2B, ACVR2B-AS1,AD000090.2, AD000864.1, AD000864.5, ADAD2, ADAM11, ADAM12, ADAM19,ADAM2, ADAM23, ADAM33, ADAM7, ADAM8, ADAMTS10, ADAMTS12, ADAMTS13,ADAMTS15, ADAMTS16, ADAMTS17, ADAMTS18, ADAMTS19, ADAMTS2, ADAMTS20,ADAMTS6, ADAMTS7, ADAMTS8, ADAMTS9, ADAMTS9-AS1, ADAMTS9-AS2, ADAMTSL1,ADAMTSL3, ADAMTSL4, ADAMTSL5, ADAP1, ADARB2, ADCK1, ADCY2, ADCY3, ADCY5,ADCY6, ADCY8, ADCYAP1R1, ADD1, ADD2, ADH1A, ADH1B, ADH5P3, ADH6,ADORA2A, ADRA2B, ADRA2C, ADRB1, ADRBK1, ADSL, AE000658.27, AE000659.23,AEBP1, AES, AF013593.1, AF038458.5, AF064858.6, AF064863.1, AF121898.1,AF131217.1, AF146191.4, AF165138.7, AF196970.3, AF235103.1, AF238380.3,AF238380.5, AFAP1, AFAP1L1, AFAP1L2, AFF2, AFF3, AFG3L2P1, AFMID, AFP,AGAP11, AGAP1-IT1, AGAP2, AGAP7, AGBL4-IT1, AGFG2, AGPAT1, AGPAT4, AGR2,AGRN, AGT, AGTR1, AGXT2L2, AHCY, AHDC1, AHNAK, AHSG, AIF1L, AIFM3,AIM1L, AIM2, AIP, AIPL1, AJ003147.9, AJ006998.2, AJAP1, AJUBA, AK1,AK3P3, AK3P5, AK5, AKAP12, AKAP16BP, AKAP8L, AKNA, AKR1B1P1, AKR1B1P2,AKR1B1P7, AKR1C1, AKR1C2, AKR1C4, AKR1E2, AKT1S1, AKT2, AL008721.1,AL020996.1, AL022341.1, AL022344.7, AL022476.2, AL031005.1, AL033532.1,AL035610.2, AL049542.1, AL049610.1, AL049840.1, AL078621.4, AL078621.5,AL117340.1, AL121578.7, AL121952.1, AL132768.1, AL132772.1, AL133458.1,AL133492.3, AL137145.1, AL137145.2, AL158069.1, AL158835.1, AL161626.1,AL161652.1, AL161772.1, AL161908.1, AL161915.1, AL162151.3, AL162458.1,AL163953.3, AL353671.4, AL353698.1, AL353791.1, AL353898.1, AL353898.3,AL355149.1, AL355388.1, AL356475.1, AL356776.1, AL357515.1, AL358813.1,AL359851.1, AL365502.1, AL391421.1, AL445199.1, AL512355.4, AL590233.1,AL590763.5, AL591025.1, AL591069.1, AL591845.1, AL592494.4, AL592528.1,AL645728.1, AL645728.2, AL672183.2, ALDH16A1, ALDH1A1, ALDH1L1-AS2,ALDH2, ALDH3A1, ALDH3B2, ALDH4A1, ALDH7A1, ALDH7A1P1, ALG12, ALG1L,ALKBH7, ALMS1-IT1, ALMS1P, ALOX15, ALPK2, ALPL, ALPP, ALX3, AMBP,AMBRA1, AMDHD1, AMDHD2, AMELY, AMH, AMHR2, AMICA1, AMIGO2, AMMECR1L,AMN, AMOT, AMOTL1, AMOTL2, AMPH, AMT, ANAPC11, ANG, ANGPT1, ANGPT2,ANK1, ANK2, ANK3, ANKDD1A, ANKFN1, ANKLE1, ANKRD1, ANKRD13B, ANKRD13D,ANKRD18B, ANKRD18CP, ANKRD20A10P, ANKRD20A11P, ANKRD24, ANKRD30BL,ANKRD34B, ANKRD35, ANKRD36B, ANKRD44, ANKRD50, ANKRD53, ANKRD61,ANKRD63, ANKS1A, ANKS1B, ANKS3, ANKS4B, ANKS6, ANLN, ANO1, ANO1-AS1,ANO2, ANO3, ANO4, ANO6, ANO7L1, ANO8, ANO9, ANP32AP1, ANP32BP3, ANTXR2,ANXA1, ANXA10, ANXA13, ANXA2R, ANXA4, AOAH, AOF2, AOX1, AP000251.2,AP000266.7, AP000269.1, AP000275.65, AP000320.6, AP000322.53,AP000344.3, AP000344.4, AP000345.1, AP000345.2, AP000345.4, AP000346.2,AP000347.4, AP000350.4, AP000354.4, AP000355.2, AP000356.2, AP000357.4,AP000361.2, AP000462.3, AP000640.10, AP000640.8, AP000662.4, AP000692.9,AP000721.4, AP000765.1, AP000797.3, AP000807.1, AP000857.1, AP000867.1,AP000997.1, AP001055.6, AP001056.1, AP001065.15, AP001092.5, AP001187.1,AP001347.6, AP001439.2, AP001468.1, AP001468.58, AP001469.5, AP001469.9,AP001615.9, AP001623.1, AP001626.2, AP001628.6, AP001877.1, AP002380.1,AP002387.1, AP002954.3, AP003068.12, AP003068.23, AP003068.9,AP003419.15, AP003419.16, AP003774.4, AP004290.1, AP005482.1,AP006216.10, AP006216.11, AP006216.12, AP006285.1, AP006285.6, AP1G2,AP1M1, AP1M2, AP1S1, AP2A2, AP2S1, AP3B2, AP3S1, APBA2, APBB1, APC2,APCDD1, APEH, APEX1, APLP1, APOA1, APOA1BP, APOA2, APOA4, APOB,APOBEC3A, APOBEC3D, APOBEC3F, APOC1, APOC2, APOC3, APOE, APOH, APOM,APOPT1, APRT, AQP10, AQP11, AQP5, AQP6, AQP7, AQP7P2, AQP7P3, AQP8,ARAP2, ARC, ARD1A, ARF1P2, ARFGAP2, ARG1, ARGLU1, ARHGAP10, ARHGAP15,ARHGAP17, ARHGAP22, ARHGAP23, ARHGAP28, ARHGAP33, ARHGAP35, ARHGAP36,ARHGAP39, ARHGAP4, ARHGAP40, ARHGAP42P2, ARHGAP6, ARHGAP8, ARHGAP9,ARHGDIG, ARHGEF1, ARHGEF10, ARHGEF16, ARHGEF17, ARHGEF19, ARHGEF19-AS1,ARHGEF2, ARHGEF25, ARHGEF39, ARHGEF4, ARHGEF40, ARHGEF7-AS1, ARID1A,ARID3A, ARID3B, ARID3C, ARIH2, ARL10, ARL2, ARL2BPP10, ARL3, ARL5AP4,ARMC12, ARMC3, ARMC5, ARMCX6, ARNT2, ARNTL2, ARPC4-TTLL3, ARPP21, ARRB1,ARRDC1, ARSA, ARSFP1, ARS1, ART5, ARTN, ARVCF, ARX, AS3MT, ASAP2, ASAP3,ASCL1, ASGR1, ASGR2, ASIC1, ASIC2, ASIC3, ASIC4, ASIP, ASL, ASPSCR1,ASS1, ASS1P1, ASS1P10, ASS1P11, ASS1P4, ASS1P5, ASS1P7, ASS1P9, ASTN1,ASTN2, ATCAY, ATG16L2, ATG2A, ATG4B, ATG9A, ATG9B, ATHL1, ATN1, ATOH8,ATP11C, ATP12A, ATP13A1, ATP13A2, ATP13A5, ATP13A5-AS1, ATP1A2, ATP1A3,ATP1A4, ATP1B2, ATP2A1, ATP2B1, ATP2B2, ATP2B3, ATP2C2, ATP4B, ATP5A1P3,ATP5C1P1, ATP5G1P4, ATP5G1P8, ATP5G2, ATP5G2P1, ATP5G2P3, ATP5LP2,ATP5SL, ATP6V0C, ATP7B, ATP8A2, ATP8B1, ATP8B2, ATP8B3, ATPAF1,ATPAF1-AS1, ATRIP, ATXN2L, ATXN7L1, ATXN7L2, ATXN7L3, AURKB, AURKC,AUTS2, AVP, AVPR1B, AVPR2, AXIN1, AXIN2, AXL, AZI1, AZU1, B3GALT1,B3GALT6, B3GAT1, B3GAT3, B3GNT1, B3GNTL1, B4GALNT4, B4GALT5, BAALC,BAHCC1, BAI1, BAI2, BAI3, BAIAP2-AS1, BAIAP2L1, BAIAP2L2, BAMBI, BAP1,BARD1, BASP1, BAX, BBC3, BCAM, BCR3, BCAS1, BCAS3, BCAT2, BCHE, BCKDHA,BCKDHB, BCL11B, BCL2, BCL2L12, BCL7A, BCORL1, BCRP1, BCRP3, BCYRN1,BDH2, BDKRB1, BDNF, BEND4, BEND5, BGLAP, BGN, BHLHE22, BHMT, BICC1, BIK,BIN1, BIRC6, BIRC7, BLK, BLM, BLZF1, BMF, BMP1, BMP2KL, BMP3, BMP4,BMP6, BMP7, BMS1P1, BMS1P4, BNC1, BNC2, BOC, BOK-AS1, BOLA2, BOLA2B,BPHL, BPIFA1, BPIFB2, BPIFB4, BRAT1, BRD1, BRD3, BRF1, BRI3, BRI3P1,BRIP1, BRS3, BRSK2, BRWD1- AS1, BSCL2, BSG, BSN, BTBD11, BTBD17, BTBD18,BTBD2, BTBD8, BTD, BTF3P13, BTF3P14, BTF3P2, BTG2, BTN2A3P, BTNL3, BUB1,BUB1B, BVES, BVES-AS1, BX255923.1, BX322557.10, BX470102.3, BX842568.1,BX936347.1, BZRAP1, C10orf105, C10orf111, C10orf112, C10orf114,C10orf116, C10orf131, C10orf140, C10orf35, C10orf54, C10orf6, C10orf82,C10orf91, C11orf16, C11orf21, C11orf35, C11orf40, C11orf41, C11orf45,C11orf49, C11orf54, C11orf61, C11orf72, C11orf84, C11orf87, C11orf9,C12orf27, C12orf39, C12orf42, C12orf50, C12orf70, C12orf71, C12orf74,C12orf76, C14orf102, C14orf166B, C14orf169, C14orf176, C14orf180,C14orf2, C14orf23, C14orf39, C14orf80, C15orf27, C15orf38-AP3S2,C15orf62, C16orf13, C16orf54, C16orf59, C16orf68, C16orf7, C16orf71,C16orf79, C16orf85, C16orf86, C16orf87, C16orf89, C16orf92, C16orf93,C16orf95, C16orf96, C17orf103, C17orf108, C17orf109, C17orf110,C17orf47, C17orf50, C17orf53, C17orf61, C17orf62, C17orf70, C17orf75,C17orf96, C17orf98, C19orf12, C19orf24, C19orf25, C19orf33, C19orf35,C19orf48, C19orf51, C19orf54, C19orf6, C19orf60, C19orf71, C19orf73,C19orf76, C19orf80, C19orf81, C1GALT1, C1orf100, C1orf106, C1orf111,C1orf122, C1orf123, C1orf126, C1orf141, C1orf148, C1orf158, C1orf159,C1orf165, C1orf167, C1orf168, C1orf173, C1orf188, C1orf191, C1orf21,C1orf210, C1orf220, C1orf222, C1orf226, C1orf228, C1orf229, C1orf233,C1orf53, C1orf85, C1orf86, C1orf93, C1orf95, C1QL1, C1QL2, C1QL4,C1QTNF1, C1QTNF4, C1QTNF5, C1QTNF6, C1QTNF8, C1QTNF9, C1R, C1RL,C1RL-AS1, C20orf112, C20orf151, C20orf152, C20orf160, C20orf166,C20orf166-AS1, C20orf194, C20orf195, C20orf201, C20orf27, C20orf46,C20orf56, C20orf96, C21orf2, C21orf45, C21orf56, C21orf58, C21orf62,C21orf90, C22orf31, C22orf36, C22orf43, C22orf45, C2CD4C, C2CD4D,C2orf40, C2orf54, C2orf62, C2orf63, C2orf66, C2orf68, C2orf72, C2orf74,C2orf79, C2orf80, C2orf88, C3orf10, C3orf21, C3orf22, C3orf32, C3orf49,C3orf50, C3orf55, C3orf56, C3orf57, C3orf59, C3orf65, C3orf80, C4orf48,C4orf50, C4orf6, C5, C5orf13, C5orf38, C5orf4, C5orf47, C5orf52,C5orf65, C6orf108, C6orf118, C6orf123, C6orf124, C6orf134, C6orf141,C6orf163, C6orf165, C6orf183, C6orf185, C6orf192, C6orf195, C6orf59,C6orf85, C7orf26, C7orf34, C7orf50, C7orf61, C8A, C8B, C8G, C8orf16,C8orf22, C8orf31, C8orf34, C8orf44, C8orf48, C8orf49, C8orf56, C8orf73,C8orf82, C8orf86, C9orf114, C9orf123, C9orf129, C9orf16, C9orf169,C9orf170, C9orf172, C9orf173, C9orf174, C9orf45, C9orf47, C9orf50,C9orf66, C9orf69, C9orf7, C9orf89, C9orf96, CA10, CA2, CA4, CA9, CABIN1,CABLES2, CACFD1, CACHD1, CACNA1A, CACNA1B, CACNA1C, CACNA1C-AS1,CACNA1C-AS2, CACNA1C-AS4, CACNA1C-IT3, CACNA1E, CACNA1F, CACNA1H,CACNA1I, CACNA1S, CACNA2D2, CACNA2D3, CACNA2D3-AS1, CACNB1, CACNB3,CACNB4, CACNG1, CACNG2, CACNG4, CACNG6, CACNG7, CACNG8, CAD, CADM3,CADM4, CADPS2, CALB1, CALB2, CALCA, CALCB, CALCOCO1, CALCR, CALHM1,CALHM2, CALHM3, CALM3, CALML6, CALR3, CALY, CAMK1, CAMK1D, CAMK2A,CAMK4, CAMKV, CAMSAP3, CAP2, CAPG, CAPN1, CAPN10, CAPN14, CAPN5, CAPN6,CAPN9, CAPNS1, CAPS, CAPSL, CARD10, CARD14, CARD8, CARHSP1, CARM1,CASC5, CASKIN1, CASKIN2, CASP16, CASP3, CASZ1, CATSPERG, CAV1, CAV2,CBFA2T2, CBFA2T3, CBLB, CBLC, CBLN1, CBLN2, CBLN3, CBLN4, CBR3,CBR3-AS1, CBS, CBWD7, CBX1, CBX1P1, CBX2, CBX3P4, CBX3P5, CBX5, CBX6,CBX8, CC2D1A, CCBL1, CCBP2, CCDC101, CCDC102A, CCDC106, CCDC107,CCDC116, CCDC128, CCDC135, CCDC136, CCDC13-AS1, CCDC14, CCDC142,CCDC144NL, CCDC148, CCDC150, CCDC151, CCDC153, CCDC154, CCDC157,CCDC160, CCDC162P, CCDC169, CCDC171, CCDC22, CCDC23, CCDC24, CCDC27,CCDC28B, CCDC3, CCDC33, CCDC38, CCDC40, CCDC42, CCDC57, CCDC58, CCDC60,CCDC62, CCDC63, CCDC64, CCDC65, CCDC68, CCDC69, CCDC71, CCDC71L,CCDC74A, CCDC74B, CCDC74B-AS1, CCDC78, CCDC8, CCDC80, CCDC85A, CCDC88B,CCDC88C, CCDC92, CCDC96, CCDC99, CCHCR1, CCK, CCKAR, CCL1, CCL14, CCM2,CCNA1, CCNB1, CCNB2, CCNF, CCNJL, CCNJP2, CCNT2P1, CCR9, CCT5, CCT6B,CD109, CD164L2, CD2, CD247, CD248, CD276, CD300A, CD320, CD36, CD37,CD3G, CD7, CD79A, CD8B, CD99, CDAN1, CDC20, CDC20P1, CDC25A, CDC25B,CDC25C, CDC42BPB, CDC42EP1, CDC42EP2, CDC42-IT1, CDC45, CDCA3, CDCA7,CDCA7L, CDCA8, CDCP2, CDH10, CDH11, CDH12, CDH12P4, CDH13, CDH15, CDH16,CDH17, CDH2, CDH20, CDH23, CDH24, CDH3, CDH4, CDH7, CDH8, CDH9, CDHR2,CDHR3, CDHR5, CDIPT, CDK10, CDK16, CDK18, CDK3, CDK5, CDK9, CDKAL1,CDKN2AIPNLP2, CDKN2D, CDKN3, CDO1, CDR1, CDR2L, CDRT15, CDS1, CDT1,CDX2, CDY4P, CDYL2, CEACAM1, CEACAM16, CEACAM19, CEACAMP2, CEBPA,CEBPA-AS1, CECR2, CECR6, CECR7, CELF3, CELF5, CELSR1, CELSR2, CELSR3,CEMP1, CEND1, CENPA, CENPE, CENPF, CENPI, CENPJ, CENPK, CENPM, CENPO,CENPT, CENPV, CENPVP1, CENPVP2, CENPVP3, CENTA1, CEP135, CEP164,CEP170P1, CEP250, CEP55, CEP78, CER1, CERCAM, CERS1, CERS4, CES5AP1,CFD, CFHR5, CFL1, CFL1P1, CFL1P2, CFL1P6, CFP, CGA, CGN, CGNL1, CGREF1,CHAC1, CHAT, CHCHD5, CHCHD6, CHD5, CHD8, CHFR, CHGA, CHID1, CHKA,CHMP1A, CHMP6, CHN2, CHORDC2P, CHRD, CHRFAM7A, CHRM2, CHRM3-AS2, CHRM5,CHRNA2, CHRNA4, CHRNA7, CHRNB4, CHRND, CHRNE, CHST1, CHST12, CHST13,CHST14, CHST3, CHST5, CHST6, CHST7, CHST9-AS1, CHSY3, CHTF18, CIAPIN1,CIAPIN1P, CIB2, CIC, CICP13, CILP, CILP2, CIP29, CISD3, CIT, CITED4,CIZ1, CKAP2, CKAP2L, CKB, CKM, CKMT2, CKS1BP6, CKS2, CLASP1, CLASRP,CLCF1, CLCN1, CLCN2, CLCN5, CLCN6, CLCN7, CLCNKA, CLCNKB, CLCP2, CLDN1,CLDN11, CLDN15, CLDN18, CLDN19, CLDN20, CLDN6, CLDND2, CLEC11A, CLEC16A,CLEC2D, CLEC3B, CLIC1, CLIC1P1, CLIC3, CLIC4, CLIC5, CLIP2, CLIP3, CLN3,CLPP, CLRN1-AS1, CLRN3, CLSPN, CLSTN2, CLSTN3, CLTC-IT1, CLU, CLVS2,CMTM1, CMTM2, CMTM3, CMYA5, CNDP1, CNFN, CNGA1, CNGA4, CNGB1, CNGB3,CNIH2, CNIH3, CNN1, CNN2, CNN3, CNOT6, CNPY1, CNPY3, CNPY4, CNR1, CNTD2,CNTF, CNTFR, CNTLN, CNTN2, CNTN3, CNTNAP2, CNTNAP3, CNTNAP3B, CNTNAP4,CNTNAP5, COBRA1, COCH, COL11A1, COL12A1, COL14A1, COL18A1, COL19A1,COL1A1, COL1A2, COL21A1, COL22A1, COL23A1, COL25A1, COL2A1, COL3A1,COL4A1, COL4A2, COL4A2-AS1, COL4A2-AS2, COL4A5, COL4A6, COL5A1, COL5A2,COL6A1, COL6A2, COL6A4P2, COL6A6, COL7A1, COL8A2, COL9A1, COL9A2,COL9A3, COLQ, COMMD4, COMT, COPS5P, COQ2, COQ4, CORIN, CORO1A, CORO1B,CORO2A, CORO2B, COTL1, COX10, COX11, COX4I2, COX5BP6, COX6B2, COX8C,CPAMD8, CPB2, CPB2-AS1, CPM, CPN1, CPNE1, CPNE2, CPNE5, CPNE7, CPNE9,CPS1, CPSF1, CPSF1P1, CPSF4, CPT1B, CPT1C, CPVL, CPXM1, CPZ, CR1,CR769776.4, CRABP1, CRAT, CRB1, CRB2, CREB3L3, CRELD1, CRH, CRHBP,CRHR1, CRHR2, CRIP3, CRISPLD1, CRISPLD2, CRMP1, CRNDE, CROCC, CRTAC1,CRTAM, CRTC1, CRYBA2, CRYBA4, CRYBB1, CRYBB3, CRYGD, CRYGN, CRYM,CRYM-AS1, CRYZP1, CSAD, CSDC2, CSF1, CSF2RA, CSF3, CSF3R, CSK, CSMD1,CSMD2, CSMD3, CSNK1A1P1, CSNK1E, CSNK1G2, CSPG4, CSPG4P5, CSPG5, CSRNP3,CSRP2, CST1, CST3, CST9LP1, CTA- 134P22.2, CTA-150C2.13, CTA-221G9.10,CTA-221G9.11, CTA-221G9.7, CTA- 250D10.19, CTA-250D10.23, CTA-254O6.1,CTA-256D12.12, CTA-282F2.3, CTA- 30512.1, CTA-331F8.1, CTA-373H7.7,CTA-384D8.20, CTA-384D8.31, CTA- 407F11.6, CTA-445C9.15, CTA-796E4.4,CTA-85E5.10, CTA-929C8.6, CTA- 941F9.9, CTA-963H5.5, CTA-984G1.5,CTAGE15P, CTB-113P19.1, CTB- 113P19.4, CTB-118P15.2, CTB-127C13.1,CTB-129P6.4, CTB-134H23.1, CTB- 161M19.2, CTB-171A8.1, CTB-174D11.1,CTB-174D11.2, CTB-175E5.7, CTB- 178M22.2, CTB-17P3.4, CTB-181F24.1,CTB-186G2.1, CTB-186H2.3, CTB- 25B13.12, CTB-25B13.6, CTB-25B13.9,CTB-31O20.8, CTB-33O18.3, CTB- 35F21.3, CTB-37A13.1, CTB-41I6.2,CTB-43E15.4, CTB-47B11.3, CTB-49A3.2, CTB-49A3.4, CTB-50L17.10,CTB-50L17.5, CTB-55O6.12, CTB-58E17.5, CTB- 58E17.9, CTB-66B24.1,CTB-78F1.1, CTB-79E8.2, CTB-85P21.2, CTB-88F18.3, CTBP2P1, CTC-209H22.2,CTC-210G5.1, CTC-215O4.4, CTC-218H9.1, CTC- 232P5.1, CTC-232P5.3,CTC-232P5.4, CTC-235G5.2, CTC-235G5.3, CTC-250I14.6, CTC-250P20.1-001,CTC-260E6.8, CTC-260F20.7, CTC-265N9.1, CTC-268N12.2, CTC-268N12.3,CTC-278L1.1, CTC-281F24.1, CTC-297N7.1, CTC-297N7.7, CTC- 304I17.5,CTC-325H20.2, CTC-325J23.3, CTC-325L16.1, CTC-327F10.4, CTC- 329D1.2,CTC-338M12.7, CTC-338M12.9, CTC-340A15.2, CTC-360G5.1, CTC- 367F4.1,CTC-367J11.1, CTC-378H22.2, CTC-379B2.4, CTC-398G3.1, CTC- 425O23.2,CTC-429L19.3, CTC-451P13.1, CTC-454I21.4, CTC-455F18.3, CTC- 458I2.2,CTC-462L7.1, CTC-463N11.3, CTC-467M3.1, CTC-470C15.1, CTC- 478M6.1,CTC-479C5.10, CTC-479C5.11, CTC-484M2.1, CTC-497E21.3, CTC- 497E21.4,CTC-507E12.1, CTC-510F12.2, CTC-510F12.4, CTC-518P12.6, CTC- 523E23.1,CTC-535M15.2, CTC-548K16.5, CTC-558O2.1, CTC-558O2.2, CTC- 575I10.1,CTC-756D1.1, CTC-756D1.2, CTC-786C10.1, CTD-2001E22.2, CTD- 2008L17.1,CTD-2008L17.2, CTD-2011F17.2, CTD-2012K14.1, CTD-2012K14.2,CTD-2012K14.3, CTD-2012K14.6, CTD-2012M11.3, CTD-2020K17.1, CTD-2020K17.3, CTD-2021A8.2, CTD-2026D20.2, CTD-2027G2.1, CTD-2033A16.2,CTD-2033D15.1, CTD-2034I4.2, CTD-2035E11.3, CTD-2044J15.1, CTD-2047H16.4, CTD-2049J23.2, CTD-2054N24.1, CTD-2054N24.2, CTD-2073O6.1,CTD-2083E4.4, CTD-2085J24.4, CTD-2089N3.1, CTD-2089N3.2, CTD-2089N3.3,CTD-2090I13.2, CTD-2095E4.2, CTD-2102P23.1, CTD-2104P17.2, CTD-2116F7.1,CTD-2132N18.2, CTD-2134A5.3, CTD-2134A5.4, CTD-2145A24.4, CTD-2147F2.1,CTD-2152M20.2, CTD-2173J9.3, CTD-2173L22.4, CTD-2184D3.1, CTD-2189E23.1, CTD-2192J16.11, CTD-2194D22.3, CTD-2194D22.4, CTD-2196E14.3,CTD-2196E14.4, CTD-2196E14.5, CTD-2199O4.3, CTD-2201E18.3, CTD-2201G16.1, CTD-2201G3.1, CTD-2201I18.1, CTD-2206G10.1, CTD-2206N4.4,CTD-2223O18.1, CTD-2224J9.7, CTD-2227C6.2, CTD-2228K2.7, CTD-2230M5.1,CTD-2231H16.1, CTD-2235C13.1, CTD-2235C13.2, CTD-2258A20.5, CTD-2262B20.1, CTD-2265O21.7, CTD-2269E23.2, CTD-2270L9.4, CTD-2281E23.1,CTD-2290C23.1, CTD-2290P7.1, CTD-2293H3.1, CTD-2297D10.2, CTD-2298J14.2, CTD-2301A4.1, CTD-2311M21.2, CTD-2320G14.2, CTD-2320O4.2,CTD-2330K9.3, CTD-2335O3.3, CTD-2336H13.1, CTD-2339F6.1, CTD-2339L15.3,CTD-2342J14.6, CTD-2358C21.4, CTD-2373J6.1, CTD-2376I20.1, CTD-2383M3.1,CTD-2514K5.4, CTD-2515A14.1, CTD-2515H24.4, CTD-2516F10.2, CTD-2517M14.5, CTD-2517M22.14, CTD-2517M22.16, CTD-2517M22.17, CTD-2517O10.5, CTD-2518G19.3, CTD-2523D13.2, CTD-2524L6.2, CTD-2528L19.4,CTD-2530H12.4, CTD-2530H12.7, CTD-2530H12.8, CTD-2532D12.4, CTD-2536I1.1, CTD-2538A21.1, CTD-2540B15.11, CTD-2540B15.7, CTD-2540B15.8,CTD-2540B15.9, CTD-2541J13.2, CTD-2542C24.1, CTD-2542L18.1, CTD-2547G23.2, CTD-2547H18.1, CTD-2552B11.2, CTD-2555K7.2, CTD-2561B21.3,CTD-2561B21.7, CTD-2562J15.4, CTD-2562J15.6, CTD-2562J17.7, CTD-2562J17.9, CTD-2576D5.4, CTD-2576F9.2, CTD-2583A14.1, CTD-2587H24.5,CTD-2588C8.6, CTD-2589H19.4, CTD-2589M5.5, CTD-2600O9.1, CTD-2611K5.6,CTD-2616J11.4, CTD-2621I17.6, CTD-2623N2.5, CTD-2632K10.1, CTD-2639E6.4,CTD-2647L4.1, CTD-2647L4.4, CTD-2651B20.1, CTD-2651C21.3, CTD-2655K5.1,CTD-2659N19.10, CTD-2659N19.2, CTD-2659N19.9, CTD-3006G17.2, CTD-3025N20.2, CTD-3032H12.1, CTD-3051D23.1, CTD-3060P21.1, CTD-3064H18.1,CTD-3065J16.6, CTD-3065J16.9, CTD-3074O7.5, CTD-3080P12.3, CTD-3088G3.6,CTD-3096M3.2, CTD-3105H18.7, CTD-3105H18.9, CTD-3113P16.5, CTD-3113P16.7, CTD-3118D7.1, CTD-3126B10.1, CTD-3148I10.1, CTD-3179P9.2,CTD-3203P2.1, CTD-3233P19.1, CTDP1, CTDSP1, CTF1, CTGF, CTHRC1, CTNNAL1,CTNNBIP1, CTNND2, CTNS, CTPS2, CTRL, CTSD, CTSE, CTSL1P2, CTSL1P3, CTTN,CTXN1, CUBN, CUEDC2, CUL1, CUL7, CUL9, CUX2, CX3CL1, CXADR, CXCL1,CXCL11, CXCL12, CXCL14, CXCL6, CXCR7, CXorf30, CXorf31, CXorf58,CXorf68, CXorf69, CXXC4, CYB5R2, CYB5R3, CYBA, CYGB, CYHR1, CYLN2, CYMP,CYP11A1, CYP24A1, CYP26B1, CYP27C1, CYP2C19, CYP2C9, CYP2D6, CYP2D7P1,CYP2E1, CYP2F1P, CYP2S1, CYP2W1, CYP3A4, CYP46A1, CYP4A22-AS1, CYP4B1,CYP4F27P, CYP4F29P, CYP4F30P, CYP4F31P, CYP4F35P, CYP4X1, CYP51P3,CYP7B1, CYP8B1, CYR61, CYSLTR2, CYTH1, CYTH2, CYTH3, CYTH4, CYTL1,DAAM2, DAB1, DAB2, DAB2IP, DACT1, DACT2, DACT3, DACT3-AS1, DAGLA, DAGLB,DALRD3, DAND5, DAO, DAPK3, DARC, DBC1, DBF4B, DBH, DBH-AS1, DBIP1, DBN1,DBNDD1, DBNL, DBX2, DCAF12L1, DCAF12L2, DCAF15, DCAF4, DCBLD2, DCC,DCHS1, DCLK1, DCN, DCPS, DCTN1, DCUN1D2-AS2, DCX, DCXR, DDA1, DDAH2,DDB1, DDC, DDEF2, DDIT4L, DDN, DDX11, DDX11L1, DDX18P5, DDX18P6, DDX39A,DDX3YP1, DDX49, DDX51, DEAF1, DECR2, DEF6, DEFB109P3, DEFB115, DEGS2,DENND1A, DENND1C, DENND2A, DENND3, DENND5B-AS1, DEPDC1, DEPDC1B, DEPDC4,DEPDC7, DFNA5, DGAT1, DGAT2, DGAT2L6, DGCR6L, DGKH, DGKI, DGKK, DGKQ,DHCR24, DHCR7, DHDH, DHFR, DHODH, DHPS, DHRS1, DHRS13, DHRS3, DHRSX,DHX34, DIAPH2-AS1, DIAPH3, DIO3, DIO3OS, DIRAS3, DIRC3, DISP2,DKEZp761P0423, DKK1, DKK2, DKK3, DKKL1, DKKL1P1, DLEC1, DLEU7, DLG4,DLG5, DLGAP1, DLGAP2, DLGAP3, DLGAP5, DLK1, DLL1, DLL3, DLL4, DLX2,DLX3, DMAP1, DMBT1, DMD, DMD-AS1, DMD-AS2, DMKN, DMPK, DMRT2, DMRTC1,DMRTC1B, DMWD, DNAAF3, DNAH1, DNAH10, DNAH10OS, DNAH11, DNAI2, DNAJB13,DNAJB5, DNAJC11, DNAJC17, DNAJC27-AS1, DNAJC4, DNAL4, DNALI1, DNASE1,DNASE1L1, DNASE1L3, DNM1P46, DNMBP, DNMBP-AS1, DNMT3A, DOC2A, DOC2B,DOC2GP, DOCK2, DOCK5, DOCK6, DOCK7, DOCK8, DOK1, DOK4, DOK5, DOK6, DOLK,DOPEY2, DPEP1, DPF1, DPF3, DPP10, DPP3, DPP4, DPPA4, DPY19L2P1, DPYD,DPYSL3, DPYSL4, DPYSL5, DQX1, DRAP1, DRAXIN, DRD1, DRD1IP, DRD2, DRD4,DRD5, DRP2, DSC2, DSC3, DSCAM, DSCAM-IT1, DSCAML1, DSCR6, DSCR9, DSEL,DSG2, DSG4, DTL, DTX1, DTX3, DTX4, DUOX1, DUSP1, DUSP10, DUSP12, DUSP15,DUSP18, DUSP22, DUSP6, DUSP8, DUSP9, DUT, DUTP2, DUTP6, DVL2, DYNLRB2,DYRK1B, DYSF, DZANK1, E2F1, E2F2, E2F5, E2F7, E2F8, E4F1, EBF1, EBF2,EBF3, EBF4, EBP, ECE1, ECH1, EDAR, EDC4, EDG4, EEF1A1P12, EEF1A1P3,EEF1A1P31, EEF1B2P1, EEF1DP1, EEF2, EFCAB1, EFCAB4A, EFCAB4B, EFCAB8,EFEMP1, EFEMP2, EFHD2, EFNA1, EFNA2, EFNA3, EFNA4, EFNB1, EFNB2, EFNB3,EGFEM1P, EGFL6, EGFL7, EGLN2, EGLN3, EGR1, EHD2, EHMT1, EIF2AK4, EIF2S2,EIF2S2P2, EIF3C, EIF4A1, EIF4A1P6, EIF4A1P7, EIF4BP2, EIF4EBP3, EIF5AP4,ELAVL2, ELAVL3, ELF4, ELF5, ELFN1, ELFN2, ELMO1-AS1, ELMOD1, ELOVL2,ELOVL2-AS1, ELP6, EMC10, EME2, EMID1, EMID2, EMILIN1, EMILIN2, EMILIN3,EML2, EMX2, EN2, ENC1, ENDOG, ENGASE, ENHO, ENO4, ENPEP, ENPP1, ENPP6,ENTHD2, ENTPD6, ENTPD8, EP300, EPB42, EPB49, EPHA1, EPHA10, EPHA3,EPHA4, EPHA6, EPHA7, EPHB1, EPHB2, EPHB3, EPHB4, EPHB6, EPHX3, EPN1,EPN3, EPOR, EPPK1, EPS15L1, EPS8, EPS8L1, EPS8L2, EPS8L3, ERBB2, ERBB3,ERBB4, ERC2, ERCC2, ERF, ERGIC3, ERI3, ERI3-IT1, ERN1, ERN2, ERRFI1-IT1, ERVMER34-1, ESPL1, ESPN, ESPNL, ESRP2, ESRRAP1, ESRRB, ESYT3,ETNK2, ETV1, ETV3L, ETV4, ETV6, EVC, EVC2, EVI2A, EVL, EXD3, EXO1,EXOC3L1, EXOC3L4, EXOC7, EXOSC10, EXOSC5, EXT1, EXTL1, EXTL2, EYA1,EYA2, EYA4, EZH2, EZH2P1, F10, F10-AS1, F2, F2R, F2RL2, F5, F7, FABP3,FABP5, FABP5P1, FABP5P2, FABP5P7, FABP6, FABP7, FABP7P1, FADS2, FADS6,FAH, FAHD2B, FAHD2CP, FAIM2, FAM100B, FAM101A, FAM101B, FAM107B,FAM108A1, FAM108A5P, FAM108A6P, FAM109A, FAM110B, FAM110D, FAM111B,FAM113A, FAM115B, FAM116B, FAM117B, FAM122C, FAM123A, FAM125A, FAM125B,FAM126A, FAM127A, FAM127C, FAM129C, FAM131A, FAM131B, FAM131C, FAM132A,FAM136A, FAM138B, FAM154B, FAM155B, FAM156B, FAM157A, FAM157C, FAM159A,FAM163A, FAM166B, FAM168B, FAM171A2, FAM175A, FAM176B, FAM179A, FAM180B,FAM181B, FAM184A, FAM185A, FAM185BP, FAM186B, FAM188A, FAM189A1,FAM189A2, FAM189B, FAM18A, FAM193A, FAM194A, FAM195B, FAM196A, FAM196B,FAM198A, FAM198B, FAM19A1, FAM19A5, FAM201B, FAM203A, FAM203B, FAM20A,FAM211B, FAM212B, FAM213B, FAM215B, FAM21B, FAM220CP, FAM221B, FAM227A,FAM228A, FAM22A, FAM22E, FAM22F, FAM22G, FAM27D1, FAM27E2, FAM32A,FAM3D, FAM40A, FAM43B, FAM46B, FAM57A, FAM57B, FAM58BP, FAM58DP, FAM59B,FAM5B, FAM5C, FAM60BP, FAM60CP, FAM64A, FAM65A, FAM65B, FAM65C, FAM66B,FAM66C, FAM66D, FAM69B, FAM70B, FAM71E1, FAM72B, FAM76B, FAM78A, FAM83A,FAM83B, FAM83D, FAM83F, FAM83H, FAM84A, FAM86B1, FAM86B2, FAM86C2P,FAM86FP, FAM86GP, FAM86HP, FAM86JP, FAM86KP, FAM89A, FAM89B, FAM90A1,FAM92B, FAM99B, FANCA, FANCE, FANCG, FANCI, FAR1-IT1, FARP1, FARP1-AS1,FARP2, FASN, FAT2, FAT3, FATE1, FBLIM1, FBLL1, FBLN1, FBLN2, FBLN5,FBLN7, FBN1, FBN2, FBN3, FBP2, FBRS, FBRSL1, FBXL10, FBXL12, FBXL19,FBXL19-AS1, FBXL20, FBXL21, FBXL22, FBXL7, FBXO10, FBXO15, FBXO2,FBXO24, FBXO40, FBXO44, FBXO5, FBXW4, FBXW9, FCGR1A, FCGR2B, FCGRT,FCHO1, FCHSD1, FCHSD2, FCRLB, FDFT1, FDX1L, FDX1P1, FDXR, FER1L4,FER1L6, FER1L6-AS2, FERMT1, FES, FEV, FEZF1, FGB, FGD1, FGD3, FGD5,FGD6, FGF1, FGH11, FGF12, FGF12-AS2, FGF12-AS3, FGF13, FGF13- AS1,FGF14, FGF17, FGF18, FGF5, FGFR1, FGFR2, FGFR3, FGFR3P6, FGFR4, FGFRL1,FHAD1, FHIT, FHL1, FHL2, FHL3, FHOD1, FHOD3, FIBCD1, FIBP, FIG.N, FIS1,FITM1, FJX1, FKBP10, FKBP1B, FKBP8, FKBP9, FKBP9L, FKRP, FLJ13305,FLJ23834, FLJ25404, FLJ31568, FLJ34690, FLJ37228, FLJ44048, FLJ44124,FLJ44342, FLJ46309, FLNA, FLNC, FLOT2, FLRT1, FLRT2, FLRT3, FLYWCH1,FLYWCH2, FMNL1, FMNL2, FMO1, FN1, FNDC1, FNDC4, FNDC8, FOLR1, FOS, FOSB,FOXA1, FOXA3, FOXB1, FOXD3, FOXD4L1, FOXD4L6, FOXH1, FOXI2, FOXI3,FOXJ1, FOXM1, FOXO3B, FOXO4, FOXP1-AS1, FOXP3, FOXP4, FOXRED1, FPGS,FRAT1, FRAT2, FREM1, FREM2, FRMD4A, FRMD4B, FRMD5, FRMD6, FRMD8P1,FRMPD2, FRMPD3, FSCN1, FSCN2, FSCN3, FSD1, FSIP2, FST, FSTL1, FSTL3,FSTL5, FTCD, FTCD-AS1, FTH1P15, FTH1P5, FTL, FTLP12, FTLP3, FTOP1, FTX,FUOM, FUT1, FUT6, FUT9, FUZ, FXYD3, FXYD6, FXYD7, FZD2, FZD3, FZD7,FZR1, G6PC, G6PC3, GAA, GAB1, GAB2, GABARAP, GABBR2, GABRA3, GABRA5,GABRB1, GABRB2, GABRE, GABRG1, GABRG3, GABRP, GABRQ, GAGE10, GAL,GAL3ST1, GAL3ST3, GAL3ST4, GALE, GALK1, GALM, GALNS, GALNT1, GALNT13,GALNT5, GALNT6, GALNT9, GALNTL1, GALNTL4, GALNTL6, GALR1, GALR3, GALT,GAPDHP21, GAPDHP32, GAPDHP37, GAPDHP42, GAPDHP44, GAPDHP52, GAPDHP59,GAPDHP62, GAPDHP66, GAPDHP68, GAPDHS, GARNL3, GAS1, GAS2L3, GAS6,GAS6-AS1, GAS7, GAS8, GAST, GATA1, GATA3, GATA4, GATA5, GATA6, GATM,GATS, GATSL2, GATSL3, GBA2, GBAP1, GBP6, GBX1, GC, GCAT, GCDH, GCG,GCHFR, GCKR, GCLC, GCN1L1, GCNT1, GCNT2, GCNT6, GCSHP4, GDAP1L1, GDF10,GDF11, GDF5, GDF5OS, GDF6, GDPD2, GDPD3, GDPD4, GDPD5, GEMIN7, GEMIN8P4,GET4, GFER, GFI1, GFOD2, GFRA1, GFRA2, GFRA3, GGA1, GGH, GGT1, GGT3P,GGT7, GHR, GHRH, GHRL, GHRLOS, GIF, GIGYF1, GIMAP7, GINS1, GINS4, GIP,GIPC1, GIPC2, GIPR, GIT1, GJA1, GJA3, GJA9, GJB1, GJB6, GJC1, GJC2,GJC3, GJD3, GJD4, GLB1L, GLB1L2, GLDC, GLDCP, GLDN, GLI2, GLI3, GLI4,GLOD5, GLP2R, GLRA4, GLRX, GLS, GLT1D1, GLTPD1, GLTPD2, GLTSCR1,GLUD1P6, GLUL, GLULP3, GLULP4, GLYATL1, GLYATL1P1, GLYATL1P2, GLYATL2,GLYCTK, GLYCTK-AS1, GMFG, GMIP, GMNC, GNA14, GNAI2, GNAO1, GNAQP1,GNAT3, GNB1L, GNB2, GNG13, GNG3, GNG8, GNL3L, GNMT, GNRH2, GOLGA6L1,GOLGA6L10, GOLGA6L5, GOLGA6L7P, GOLGA8A, GOLGA8F, GOLGA8J, GOLIM4,GOT2P3, GPA33, GPAT2, GPATCH3, GPBAR1, GPC1, GPC2, GPC3, GPC4, GPC5,GPC5-AS1, GPC6, GPC6-AS2, GPER, GPHA2, GPM6B, GPR108, GPR111, GPR112,GPR113, GPR114, GPR119, GPR123, GPR126, GPR128, GPR133, GPR137, GPR137C,GPR141, GPR142, GPR143, GPR143P, GPR146, GPR148, GPR153, GPR156, GPR160,GPR161, GPR162, GPR173, GPR179, GPR18, GPR182, GPR26, GPR37, GPR45,GPR62, GPR64, GPR68, GPR78, GPR82, GPR83, GPR85, GPR98, GPRC5A, GPRC5B,GPRC5C, GPRIN2, GPS1, GPSM1, GPT, GPT2, GPX1, GPX7, GPX8, GRAMD1A,GRAMD2, GRAP2, GRB14, GRB7, GRHL2, GRHPR, GR1A1, GRID1, GRID2, GRID2IP,GRIK1, GRIK3, GRIK4, GRIN2C, GRIN2D, GRIN3A, GRIN3B, GRINA, GRK1, GRK4,GRK5, GRM2, GRM3, GRM5, GRM5-AS1, GRM7, GRM8, GRN, GRTP1, GRTP1-AS1,GS1-124K5.2, GS1-124K5.3, GS1- 124K5.7, GS1-124K5.8, GS1-124K5.9,GS1-256O22.3, GS1-388B5.3, GS1-421I3.4, GS1-5L10.1, GSDMB, GSG1, GSG1L,GSG2, GSPT2, GSTA4, GSTK1, GSTM1, GSTM2, GSTM5, GSTP1, GSTT1, GSTT2,GSTT2B, GSTZ1, GTDC2, GTF2F1, GTF2H2B, GTF2IP1, GTF3C5, GTSE1, GUCA1A,GUCA2B, GULOP, GULP1, GUSBP5, GUSBP8, GYG2, GYG2P1, GYPC, GYS1, H19,H1FNT, H1FX, H1FX- AS1, H2AFJ, H2AFY2, H2AFZP1, H2BFS, H3F3A, H3F3AP1,H3F3B, H3F3C, H6PD, HAAO, HABP2, HAGH, HAGHL, HAL, HAMP, HAND1, HAO2,HAP1, HAPLN3, HAPLN4, HARS, HAUS1P1, HAVCR1, HBE1, HBQ1, HCFC1, HCN1,HCN3, HCN4, HDAC1, HDAC10, HDAC11, HDAC2, HDAC6, HDAC7, HDC, HDHD1A,HEATR7B1, HEATR8, HECTD4, HECW1, HECW2, HELB, HELLS, HEPACAM, HEPACAM2,HEPH, HEPHL1, HERC2P8, HES1, HES3, HES4, HES5, HES6, HES7, HEXDC,HEXIM2, HEY2, HEYL, HFM1, HGFAC, HHEX, HHIP, HHIP-AS1, HHIPL1, HIC1,HIC2, HIF3A, HIGD1A, HIGD1AP1, HIGD2A, HIGD2B, HINT2, HIP1, HIP1R,HIPK4, HIST1H1C, HIST1H1E, HIST1H2AC, HIST1H2AE, HIST1H2AG, HIST1H2BG,HIST1H2BJ, HIST1H2BK, HIST1H2BO, HIST1H3A, HIST1H3D, HIST1H3E, HIST1H4I,HIST1H4J, HIST1H4K, HIST2H2AA3, HIST2H2AA4, HIST2H2AB, HIST2H2AC,HIST2H2BE, HIST2H3PS2, HIST2H4A, HIST3H2A, HIST3H2BB, HIST3H3, HK1, HK2,HK2P1, HK3, HKDC1, HLA-B, HLA-DQA1, HLA-DQB1, HLA-DQB1-AS1, HLTF-AS1,HM13-AS1, HMBS, HMG20B, HMGA1, HMGA1P1, HMGA1P2, HMGA1P3, HMGA1P4,HMGA2, HMGB1P10, HMGB1P24, HMGB3P22, HMGB3P32, HMGB3P8, HMGCR, HMGCS1,HMGCS2, HMGN1P26, HMGN1P35, HMGN1P4, HMGN2, HMGN2P10, HMGN2P17,HMGN2P31, HMGN2P42, HMGN3P1, HMHA1, HMP19, HMSD, HN1, HNF1A, HNF1A-AS1,HNF1B, HNF4A, HNF4G, HNRNPA1P22, HNRNPA2B1, HNRNPA3P3, HNRNPU, HOMER3,HOTAIRM1, HOXA1, HOXA2, HOXA3, HOXA4, HOXA-AS2, HOXA- AS3, HOXB2, HOXB3,HOXB-AS1, HOXB-AS3, HOXC4, HOXD1, HOXD3, HOXD-AS1, HPCAL1, HPD, APDL,HPN, HPS1, HPSE, HRASLS5, HRC, HRH2, HRH3, HRK, HS1BP3, HS3ST3A1,HS3ST3B1, HS3ST4, HS3ST5, HS3ST6, HS6ST1, HS6ST1P1, HS6ST3,hsa-mir-3187, hsa-mir-3195, HSBP1, HSD11B1L, HSD11B2, HSD17B14, HSD17B2,HSD3B1, HSD3B7, HSF2BP, HSPA12B, HSPB2, HSPB8, HSPBP1, HSPD1P21, HSPG2,HTR1A, HTR1B, HTR1E, HTRA1, HTT, HUNK, HYAL1, HYAL2, HYAL3, HYI-AS1,ID3, IDH1, IDH1-AS1, IDH2, IDH3B, IDH3G, IDI1, IDI2-AS1, IDUA, IER2,IER5L, IFI6, IFITM1, IFITM10, IFITM3, IFITM5, IFNWP19, IFT140, IFT27,IGBP1P3, IGDCC3, IGDCC4, IGF1, IGF2, IGF2BP1, IGF2BP2, IGF2BP3, IGFALS,IGFBP1, IGFBP2, IGFBP5, IGFBPL1, IGFL1, IGFL4, IGFLR1, IGLON5, IGLV7-43,IGLV7-46, IGSF10, IGSF21, IGSF22, IGSF23, IGSF3, IGSF8, IGSF9, IHH,IKBKE, IL11RA, IL12A, IL12B, IL13, IL15, IL16, IL17C, IL17RD, IL1RAP,IL1RAPL1, IL23R, IL27RA, IL28RA, IL31RA, IL32, IL34, IL4R, IL6STP1,ILF3, ILVBL, IMPA2, IMPDH1P4, INF2, ING4, INHA, INMT, INO80, INPP5E,INPP5J, INPPL1, INSR, INTS1, INTS3, INTS9, IPO9, IPW, IQCA1, IQCC, IQCE,IQCJ-SCHIP1, IQGAP2, IQGAP3, IQSEC3, IRF3, IRX1, IRX2, IRX3, IRX4, IRX5,ISG15, ISL1, ISLR2, ISOC2, ISPD, ISX, ISYNA1, ITGA11, ITGA2B, ITGA6,ITGA7, ITGA8, ITGAL, ITGB4, ITGB5, ITGB6, ITGB7, ITGB8, ITGBL1, ITIH1,ITIH2, ITLN2, ITM2A, ITM2BP1, ITM2C, ITPA, ITPK1, ITPR1, ITPRIP,ITPRIPL1, IVD, IVNS1ABP, IYD, IZUMO4, J01415.7, JAK3, JAM2, JARID2,JMJD4, JMJD7-PLA2G4B, JMJD8, JPH2, JPH3, JPH4, JRK, JUN, JUP, KAL1,KALP, KALRN, KANK1, KANK2, KANK3, KANK4, KANSL1-AS1, KARSP2, KAT2A,KATNAL2, KATNB1, KAZALD1, KAZN, KB-1205A7.1, KB-1269D1.8, KB-1471A8.1,KB- 1507C5.3, KB-1507C5.4, KB-1562D12.1, KB-1562D12.2, KB-1683C8.1, KB-1896H10.1, KB-318B8.7, KBTBD12, KCNA4, KCNAB2, KCNB1, KCNC2, KCNC3,KCND1, KCND2, KCNE1L, KCNE2, KCNE3, KCNG1, KCNG2, KCNH3, KCNH5, KCNH6,KCNH8, KCNIP2, KCNIP3, KCNIP4, KCNJ12, KCNJ2, KCNJ4, KCNJ5, KCNJ6,KCNJ6-IT1, KCNK10, KCNK15, KCNMB1, KCNMB4, KCNN1, KCNN3, KCNQ1, KCNQ1DN,KCNQ1OT1, KCNQ2, KCNQ4, KCNQ5, KCNS1, KCNS2, KCNS3, KCNT1, KCNT2, KCNV1,KCNV2, KCTD11, KCTD12, KCTD15, KCTD16, KCTD17, KCTD5, KDELC1P1, KDM2B,KDM4A-AS1, KDM4B, KDM5B, KDM5B-AS1, KDM8, KEL, KHDRBS2, KHK, KHSRP,KHSRPP1, KIAA0101, KIAA0182, KIAA0195, KIAA0232, KIAA0363, KIAA0391,KIAA0427, KIAA0514, KIAA0528, KIAA0664L3, KIAA0753, KIAA0754, KIAA0895L,KIAA0913, KIAA0930, KIAA1045, KIAA1161, KIAA1211, KIAA1239, KIAA1324L,KIAA1522, KIAA1543, KIAA1545, KIAA1549, KIAA1549L, KIAA1602, KIAA1671,KIAA1683, KIAA1688, KIAA1755, KIAA1875, KIAA1984, KIAA1984-AS1, KIF11,KIF12, KIF13B, KIF14, KIF15, KIF17, KIF18A, KIF18B, KIF19, KIF1C,KIF20A, KIF21B, KIF23, KIF26A, KIF3C, KIF6, KIF7, KIFC2, KIR3DX1,KIRREL, KIRREL2, KIRREL3-AS3, KISS1R, KIT, KITLG, KLB, KLC1, KLC3, KLC4,KLF15, KLF16, KLF2, KLF4, KLF5, KLF6, KLHDC3, KLHDC7A, KLHDC8B, KLHL10,KLHL13, KLHL14, KLHL17, KLHL22, KLHL25, KLHL2P1, KLHL4, KLK10, KLK13,KLK15, KLK6, KLRC2, KLRC4, KLRC4-KLRK1, KLRG1, KLRK1, KNCN, KNDC1,KPNA3-IT1, KPRP, KPTN, KRBA1, KRBA2, KREMEN2, KRR1P1, KRT15, KRT16P3,KRT17P2, KRT18P12, KRT18P15, KRT18P20, KRT18P28, KRT18P32, KRT18P34,KRT18P5, KRT19, KRT19P1, KRT23, KRT4, KRT42P, KRT5, KRT7, KRT73, KRT81,KRT8P15, KRT8P26, KRT8P32, KRT8P36, KRT8P45, KRT8P8, KRT8P9, KRTAP5-1,KRTAP5-10, KRTAP5-2, KRTAP5-5, KRTAP5-9, KRTDAP, KTI12, L1CAM, L1TD1,L3MBTL1, LA16c-306A4.2, LA16c-312E8.2, LA16c- 313D11.10,LA16c-313D11.11, LA16c-313D11.9, LA16c-329F2.1, LA16c- 349E10.1,LA16c-360H6.3, LA16c-361A3.3, LA16c-366D3.1, LA16c-380A1.1,LA16c-381G6.1, LA16c-385E7.1, LA16c-390E6.5, LA16c-395F10.1, LA16c-395F10.2, LA16c-60G3.7, LAG3, LAMA1, LAMB1, LAMB2, LAMC1, LAMP5,LAMTOR2, LAMTOR3P1, LANCL2, LANCL3, LARGE, LARP4B, LASP1, LASS1, LASS4,LATS2, LAYN, LBX2, LBX2-AS1, LCAT, LCK, LCN12, LCN15, LCP1, LDB1, LDB2,LDHA, LDHAL6A, LDHAL6EP, LDHAP2, LDHAP3, LDHAP5, LDHB, LDHD, LDLRAD1,LDLRAD2, LECT2, LEFTY2, LEKR1, LEMD2, LENEP, LEO1, LEPRE1, LEPREL1,LEPREL2, LEPREL4, LFNG, LGALS12, LGALS14, LGALS2, LGI4, LGR6, LHCGR,LHFP, LHFPL1, LHFPL3, LHPP, LHX1, LHX3, LHX4, LHX5, LHX6, LHX9, LIG1,LILRA6, LILRB3, LILRB5, LIMD2, LIMK1, LIMK2, LIMS2, LIN28A, LIN28B,LIN7A, LIN9, LINC00029, LINC00051, LINC00086, LINC00087, LINC00158,LINC00173, LINC00174, LINC00176, LINC00202, LINC00205, LINC00208,LINC00210, LINC00261, LINC00265, LINC00304, LINC00311, LINC00313,LINC00319, LINC00333, LINC00337, LINC00338, LINC00340, LINC00341,LINC00348, LINC00379, LINC00403, LINC00404, LINC00427, LINC00458,LINC00470, LINC00479, LINC00482, LINC00487, LINC00491, LINC00501,LINC00514, LINC00515, LINC00526, LINC00539, LINC00568, LINC00577,LINC00589, LINC00595, LINC00599, LINC00605, LINC00607, LINC00614,LINC00616, LINC00618, LINC00621, LINC00634, LINC00636, LINC00638,LINC00648, LINC00649, LINC00650, LINC00652, LINC00669, LINC00672,LINGO1, LINGO3, LIPC, LIPE, LIPG, LIPJ, LIPT2, LL0XNC01-116E7.1,LL0XNC01- 221F2.2, LL0XNC01-237H1.2, LL22NC03-2H8.4, LL22NC03-86G7.1,LLGL1, LLGL2, LMBR1L, LMF1, LMF2, LMNB1, LMNB2, LMO3, LMO4, LMOD2,LMTK3, LMX1B, LOC100128326, LOC100129076, LOC100129086, LOC100129211,LOC100129905, LOC100129975, LOC100130154, LOC100130276, LOC100130886,LOC100130914, LOC100131859, LOC100132112, LOC100132491, LOC100132740,LOC100132942, LOC100133477, LOC100133516, LOC100133609, LOC100133697,LOC100133772, LOC100133923, LOC100133999, LOC100134053, LOC100134134,LOC100134144, LOC100134265, LOC100134291, LOC100134530, LOC100134634,LOC134997, LOC149134, LOC158301, LOC202781, LOC220686, LOC285074,LOC338758, LOC339290, LOC341457, LOC387934, LOC388494, LOC389332,LOC389599, LOC389634, LOC389765, LOC390705, LOC401098, LOC401357,LOC401720, LOC439953, LOC440063, LOC440926, LOC441066, LOC441268,LOC641950, LOC642299, LOC642852, LOC643313, LOC643389, LOC643911,LOC644390, LOC644596, LOC644670, LOC644914, LOC644919, LOC645233,LOC645566, LOC646044, LOC646301, LOC647346, LOC647886, LOC648526,LOC648852, LOC649841, LOC649999, LOC650157, LOC653210, LOC653505,LOC653829, LOC654244, LOC728153, LOC728440, LOC728457, LOC728492,LOC728661, LOC728728, LOC729021, LOC729120, LOC729137, LOC729660,LOC729816, LOC729970, LOC730235, LOC730284, LOC730286, LOC730740,LOC730993, LOC732360, LOC81691, LOC92659, LOC93556, LOXL1, LOXL2, LOXL3,LOXL4, LPA, LPAL2, LPAR1, LPAR2, LPAR3, LPCAT2, LPCAT4, LPHN1, LPHN2,LPHN3, LPIN3, LPPR2, LPPR5, LRAT, LRCH2, LRCH4, LRFN1, LRFN3, LRFN4,LRGUK, LRIG3, LRMP, LRP1, LRP1B, LRP2, LRP3, LRP5, LRPAP1, LRRC14,LRRC14B, LRRC16B, LRRC17, LRRC20, LRRC23, LRRC24, LRRC26, LRRC27,LRRC28, LRRC29, LRRC31, LRRC32, LRRC33, LRRC37A3, LRRC37B2, LRRC41,LRRC43, LRRC45, LRRC4B, LRRC4C, LRRC53, LRRC55, LRRC56, LRRC61, LRRC63,LRRC69, LRRC7, LRRC71, LRRC8A, LRRN1, LRRN2, LRRN4, LRRN4CL, LRSAM1,LRTM1, LRTM2, LSM3P2, LSM3P3, LSMD1, LSR, LSS, LTBP1, LTC4S, LTK, LUM,LUZP2, LY6E, LY6H, LYPD4, LYPD6, LYPD6B, LYPLA2, LYZ, LZTR1, LZTS1,LZTS2, M6PRBP1, MAB21L1, MACROD1, MACROD2-AS1, MAD1L1, MAD2L2, MADCAM1,MAFG-AS1, MAG, MAGEA4, MAGEA8, MAGEB17, MAGEC3, MAGED1, MAGED2, MAGED4,MAGED4B, MALL, MAMDC4, MAMLD1, MAMSTR, MAN1B1, MAN2B1, MAN2C1, MANEAL,MAOA, MAOB, MAP2K2, MAP2K4, MAP2K4P1, MAP2K6, MAP3K1, MAP3K10, MAP3K11,MAP3K12, MAP3K3, MAP3K4, MAP4K1, MAPK11, MAPK12, MAPK15, MAPK3, MAPK4,MAPK6, MAPK7, MAPK8IP1, MAPK8IP2, MAPK8IP3, MARCKS, MARCKSL1, MARK4,MASP1, MAST1, MAST2, MATK, MATN1, MATN2, MATN3, MATN4, MAVS, MAZ, MBD3,MBD6, MBOAT7, MCAM, MCAT, MCF2L, MCHR2, MCM10, MCM2, MCM3APAS, MCM7,MCTP1, MDFI, MDGA2, MDK, MECR, MED12, MED12L, MED14-AS1, MED16, MED22,MED24, MED25, MED27, MEF2C, MEGF10, MEGF6, MEGF8, MEIS3, MEIS3P1,MEIS3P2, MELK, MEMO1, MEMO1P1, MEN1, MEP1A, MERTK, MESTP4, MET,Metazoa_SRP, METT11D1, METTL22, METTL7B, METTL9, MEX3A, MEX3B, MEX3D,MFAP2, MFAP4, MFAP5, MFGE8, MFNG, MFSD10, MFSD2B, MFSD3, MFSD7, MGAT3,MGAT4B, MGAT4C, MGAT5B, MGC16121, MGC16384, MGC20983, MGC39900, MGLL,MGMT, MGRN1, MIAT, MICAL1, MICAL2, MICALL1, MID1IP1-AS1, MIEN1, MIER2,MIF, MIIP, MINK1, MIP, MIR103A2, MIR1203, MIR1260B, MIR1268A, MIR127,MIR1276, MIR135A1, MIR135A2, MIR137HG, MIR149, MIR181A2HG, MIR1915,MIR1972-1, MIR205HG, MIR210HG, MIR221, MIR25, MIR2682, MIR296, MIR3164,MIR3176, MIR3180-4, MIR3190, MIR31HG, MIR320E, MIR33B, MIR3615,MIR3622A, MIR3646, MIR3648, MIR3677, MIR3685, MIR3687, MIR378H, MIR3934,MIR3942, MIR421, MIR425, MIR4253, MIR4295, MIR4308, MIR431, MIR433,MIR4442, MIR4453, MIR4454, MIR4477A, MIR4479, MIR4502, MIR4504, MIR4644,MIR4650-1, MIR4686, MIR4697, MIR4730, MIR4737, MIR4750, MIR4766,MIR4768, MIR4782, MIR4783, MIR4793, MIR483, MIR486, MIR497HG, MIR503,MIR5094, MIR548I1, MIR5685, MIR573, MIR578, MIR593, MIR600HG, MIR608,MIR618, MIR619, MIR621, MIR631, MIR640, MIR643, MIR647, MIR661, MIR662,MIR762, MIR92B, MIR98, MIRLET7D, MIRLET7F1, MIRLET7G, MIXL1, MKI67,MKL1, MKNK1, MKRN3, MKRN7P, MLANA, MLL4, MLLT3, MLLT4-AS1, MLN, MLST8,MMD2, MME, MME-AS1, MMEL1, MMP11, MMP14, MMP15, MMP16, MMP17, MMP2,MMP21, MMP23A, MMP23B, MMP25, MMP26, MMRN2, MN1, MND1, MNT, MOB2, MOB3A,MOCS1P1, MOGAT2, MOK, MORG1, MORN1, MORN3, MORN4, MOSC1, MOV10, MOXD1,MOXD2P, MPL, MPND, MPPED1, MPPED2, MPST, MPZ, MPZL2, MRAP, MRC2, MRGPRF,MRPL23-AS1, MRPL28, MRPL2P1, MRPL35P2, MRPL41, MRPS26, MRPS34, MRPS36,MRPS6, MRS2P2, MRVI1, MRVI1-AS1, MS4A8B, MSANTD1, MSC, MSH4, MSI1, MSL3,MSL3L1, MSLN, MSLNL, MSMB, MSN, MSNP1, MSRA, MSRB3, MST1, MST1P2,MST1P9, MST1R, MSX2, MSX2P1, MTA1, MTCH2, MTF2, MTG1, MTHFD1L, MTHFR,MTL5, MTMR14, MTMR4, MTMR9LP, MTND1P28, MTND5P1, MTND6P21, MTNR1B,MTRNR2L1, MTRNR2L10, MTRNR2L5, MTTP, MTX1P1, MUC1, MUC16, MUC19, MUC20,MUC3A, MUC5AC, MUC5B, MURC, MUSK, MVD, MVK, MX2, MXD4, MXRA5, MXRA8,MYADML2, MYBL2, MYBPC1, MYBPC2, MYCBPAP, MYCN, MYH1, MYH10, MYH13,MYH16, MYH4, MYH7B, MYL4, MYL5, MYL6B, MYL6P2, MYL6P3, MYL9, MYLK,MYLK4, MYLK-AS1, MYO10, MYO15A, MYO15B, MYO16, MYO18A, MYO18B, MYO1A,MYO1C, MYO1G, MYO1H, MYO5C, MYO7A, MYO7B, MYO9B, MYOM2, MYOM3, MYOZ3,MZF1, MZT2A, MZT2B, N4BP2, NAA10, NAA40, NAA60, NAAA, NABP1, NACAD,NADK, NAGK, NAGLU, NAGPA, NAGS, NANOS3, NAP1L1, NAP1L4P1, NAP1L6,NAPRT1, NAPSA, NARF, NASP, NAT14, NAT6, NAV3, NBEAL2, NBPF8, NCAM1,NCAPD2P1, NCAPH, NCBP2- AS1, NCCRP1, NCF1B, NCK2, NCKAP5L, NCKIPSD,NCOA5, NCS1, NDC80, NDNF, NDOR1, NDRG2, NDST1, NDST3, NDST4, NDUFA13,NDUFA3, NDUFA7, NDUFA9P1, NDUFB11, NDUFS7, NDUFS8, NEB, NECAB2, NECAB3,NEDD9, NEFL, NEIL1, NEIL3, NEK2, NEK6, NEK8, NELL1, NES, NETO1, NETO2,NEU4, NEURL1B, NEURL2, NEUROD4, NEUROG1, NEUROG3, NFATC1, NFATC4,NFE2L3, NFRKB, NFYC, NGB, NGFR, NGFRAP1, NHLH1, NHLRC4, NHS, NHSL1,NHSL2, NICN1, NICN1-AS1, NINJ1, NINL, NIPSNAP1, NISCH, NKAIN2, NKAIN3,NKAIN4, NKD2, NKIRAS2, NKPD1, NKX2-5, NKX6-2, NKX6-3, NLGN2, NLGN3,NLGN4X, NLN, NLRP12, NLRP6, NLRP9P, NLRX1, NMBR, NME2, NME3, NME4, NME8,NMRK2, NNAT, NODAL, NOG, NOP10, NOP16, NOS1, NOS1AP, NOS2, NOS2P3,NOSIP, NOTCH1, NOTCH2, NOTCH3, NOTUM, NOVA1-AS1, NOVA2, NOX1, NOX4,NOXA1, NOXO1, NPAS1, NPAS3, NPB, NPC1L1, NPDC1, NPEPL1, NPFFR1, NPFFR2,NPHP4, NPHS1, NPHS2, NPIPL1, NPIPL2, NPM1P19, NPPB, NPR3, NPRL3, NPSR1,NPSR1-AS1, NPTX1, NPTXR, NPW, NPY1R, NPY2R, NPY5R, NR1H3, NR1H4, NR2F1,NR2F2, NR2F6, NR4A1, NR5A1, NR6A1, NRAP, NRARP, NRBP2, NREP, NRG3, NRGN,NRK, NRL, NRN1, NRSN2, NRXN2, NRXN3, NSDHL, NSFL1C, NSG1, NSRP1P1,NSUN5P1, NSUN5P2, NT5C3L, NT5DC2, NT5DC3, NT5E, NT5M, NTF3, NTF4, NTHL1,NTM, NTN3, NTN4, NTN5, NTNG1, NTNG2, NTRK3, NTS, NUBP2, NUBPL, NUCB1,NUCB1-AS1, NUDT11, NUDT14, NUDT16L1, NUDT8, NUP210P3, NUS1P2, NUTF2,NXF2, NXF3, NXN, NXPE2, NXPH2, NXPH4, NYAP1, NYNRIN, OBSCN, OBSL1, OCA2,OCM, ODF3B, ODF3L1, ODF3L2, ODZ2, ODZ3, OGG1, OIT3, OLAH, OLFM3, OLFML1,OLFML2A, OLFML3, ONECUT1, ONECUT2, ONECUT3, OPA1-AS1, OPA3, OPCML,OPLAH, OPN5, OPRK1, OPRL1, OR10D1P, OR10V2P, OR11H7, OR11Q1P, OR13C5,OR13E1P, OR13J1, OR13K1P, OR2A1, OR2A20P, OR2A3P, OR2AJ1, OR2L3, OR2L5,OR2W3, OR51E2, OR5BH1P, OR7E158P, OR7E161P, ORAI1, ORC6, OSBP2,OSBPL10-AS1, OSBPL1A, OSBPL7, OSGEPL1-AS1, OSR1, OSR2, OSTN, OTC, OTOF,OTOG, OTOP1, OTOP3, OTUB1, OTX1, OTX2, OVGP1, OVOL1, OXER1, OXLD1,P2RX1, P2RX6P, P2RY14, P2RY4, P2RY6, P4HTM, PABPC1L, PABPC1L2A,PABPC1L2B, PABPC4L, PABPN1, PABPN1L, PACS2, PACSIN3, PADI2, PAEP,PAFAH1B3, PAG1, PAGE2, PAH, PAK4, PAK7, PALD1, PALM, PALM3, PAMR1,PANK1, PANK4, PANX2, PAOX, PAPPA, PAPPA-AS1, PAPSS1, PAQR4, PAQR6,PAQR7, PAQR9, PARD6G, PARP3, PARP4P2, PARP6, PARPBP, PATZ1, PAX2, PAX3,PAX4, PAX7, PAX9, PBK, PBOV1, PBX1, PBX2, PBX2P1, PBX4, PBXIP1, PC,PCAT1, PCBP4, PCCA-AS1, PCDH10, PCDH11X, PCDH15, PCDH18, PCDH19, PCDH8,PCDH9, PCDHA1, PCDHA10, PCDHA11, PCDHA12, PCDHA13, PCDHA2, PCDHA4,PCDHA5, PCDHA6, PCDHA7, PCDHA8, PCDHA9, PCDHB19P, PCDHB2, PCDHGA10,PCDHGB4, PCDHGB6, PCDHGB8P, PCDHGC4, PCED1A, PCED1B, PCED1B-AS1, PCGF2,PCNPP, PCNT, PCOLCE, PCOLCE- AS1, PCP2, PCSK1N, PCSK4, PCSK5, PCSK6,PCYT1B, PCYT2, PDC, PDDC1, PDE11A, PDE1A, PDE1C, PDE2A, PDE3B, PDE4A,PDE4C, PDE6B, PDE6C, PDE7A, PDE9A, PDGFB, PDGFC, PDGFD, PDGFRB, PDIA2,PDK2, PDLIM3, PDLIM4, PDLIM7, PDRG1, PDSS1, PDXP, PDZD3, PDZD4, PDZK1,PDZK1P1, PDZRN4, PEBP4, PECR, PELI3, PENK, PER1, PES1P2, PEX11G, PEX6,PFDN4, PFKFB1, PFKFB4, PFKL, PFKP, PFN1P1, PFN1P3, PGA5, PGAM2, PGAM4,PGAP3, PGC, PGD, PGF, PGLS, PGLYRP1, PGM5, PGM5-AS1, PGM5P2, PGPEP1,PHACTR1, PHACTR3, PHB2, PHBP10, PHBP12, PHF1, PHF16, PHF23, PHGDH,PHLDA1, PHLDB1, PHLDB3, PHOX2A, PHPT1, PHRF1, PHTF1, PHYHD1, PI16,PI4KA, PI4KAP1, PI4KAP2, PIANP, PICK1, PID1, PIDD, PIEZO1, PIEZO2, PIF1,PIGL, PIGQ, PIGT, PIK3C2B, PIK3IP1, PIK3R1, PILRA, PIN1, PINK1, PIP4K2B,PIP5K1B, PIP5K1C, PIP5K1P1, PIP5KL1, PISD, PITX1, PITX2, PITX3, PIWIL1,PKD1, PKD1L2, PKD1P1, PKD2L1, PKDCC, PKHD1L1, PKLR, PKM, PKMP1, PKMP3,PKMP4, PKMYT1, PKN1, PKN3, PKNOX2, PKP1, PLA2G10, PLA2G12B, PLA2G2A,PLA2G4B, PLA2G4E, PLA2G4F, PLAC2, PLAC8L1, PLAGL2, PLBD2, PLCB2, PLCD1,PLCD3, PLCG1, PLCG2, PLCH1- AS2, PLCL1, PLD2, PLD3, PLD4, PLD5, PLDN,PLEC, PLEKHA8, PLEKHA9, PLEKHB1, PLEKHD1, PLEKHF1, PLEKHG1, PLEKHG2,PLEKHG3, PLEKHG4B, PLEKHG5, PLEKHG6, PLEKHG7, PLEKHH1, PLEKHH3, PLEKHJ1,PLEKHO1, PLEKHO2, PLG, PLGLA, PLGLB2, PLIN1, PLIN2, PLIN3, PLIN4, PLK1,PLK5, PLLP, PLN, PLOD1, PLS3, PLSCR3, PLSCR5, PLTP, PLXDC1, PLXDC2,PLXNA1, PLXNB1, PLXNB3, PMAIP1, PMCHL1, PMCHL2, PMEL, PMF1, PMM1, PMPCA,PNCK, PNKD, PNKP, PNMA3, PNMA6A, PNMA6C, PNMA6D, PNMT, PNOC, PNPLA3,PNPLA7, POC1B-GALNT4, PODNL1, PODXL, PODXL2, POLA1, POLD1, POLD2,POLDIP3, POLE, POLL, POLN, POLR2KP1, POM121, POM121B, POM121L9P, POMT1,POPDC2, POSTN, POTEF, POTEJ, POTEKP, POU2F2, POU3F1, POU3F2, POU3F4,POU4F1, POU5F1B, POU5F1P3, POU5F1P4, POU5F1P6, POU6F2, POU6F2-AS1,POU6F2-AS2, PPAP2B, PPAPDC3, PPARG, PPATP1, PPBPP2, PPDPF, PPEF1, PPEF2,PPFIA2, PPFIA3, PPFIA4, PPFIBP1, PPFIBP2, PPIA, PPIAL4A, PPIAP11,PPIAP21, PPIC, PPIL1P1, PPIL2, PPM1AP1, PPM1F, PPM1M, PPM1N, PPOX,PPP1CA, PPP1CC, PPP1R11P1, PPP1R14A, PPP1R16A, PPP1R16B, PPP1R17,PPP1R26, PPP1R2P10, PPP1R32, PPP1R3F, PPP1R3G, PPP2R1A, PPP2R2B,PPP2R3A, PPP2R3B, PPP2R4, PPP2R5B, PPP3CA, PPP3R2, PPP4C, PPP4R4,PPP6R2, PPY, PQLC2, PRAGMIN, PRAM1, PRAP1, PRB3, PRCD, PRDM12, PRDM13,PRDM14, PRDM16, PRDM6, PRDM8, PRDX2, PRDX2P1, PRELID1P1, PRELID2, PREX2,PRH2, PRICKLE1, PRICKLE2, PRICKLE4, PRKACG, PRKAG3, PRKAR1B, PRKCB,PRKCG, PRKCSH, PRKCZ, PRKD1, PRKD2, PRKG1, PRKG2, PRKRIP1, PRKY, PRLHR,PRMT1, PRMT8, PRO1853, PROC, PROCA1, PRODH, PRODH2, PROK1, PROM1, PROM2,ProSAPiP1, PROX1, PROX1-AS1, PRPF31, PRR12, PRR15L, PRR19, PRR22, PRR25,PRR3, PRR4, PRR5, PRR5-ARHGAP8, PRRG2, PRRG3, PRRG4, PRRT2, PRRT4,PRSS12, PRSS16, PRSS27, PRSS29P, PRSS30P, PRSS33, PRSS35, PRSS37,PRSS44, PRSS45, PRSS46, PRSS50, PRSS8, PRTFDC1, PRTG, PRTN3, PRX,PSAT1P1, PSAT1P4, PSD, PSD2, PSG1, PSG3, PSKH1, PSMC1P7, PSPN, PSRC1,PSTPIP2, PTBP2, PTCHD1, PTCHD2, PTDSS2, PTF1A, PTGER1, PTGER2, PTGER3,PTGER4, PTGES, PTGIS, PTH1R, PTK6, PTK7, PTMS, PTN, PTOV1, PTPN14,PTPN18, PTPN2P2, PTPN5, PTPN6, PTPRB, PTPRCAP, PTPRD, PTPRF, PTPRG,PTPRN2, PTPRO, PTPRQ, PTPRR, PTPRS, PTPRT, PTPRVP, PTPRZ1, PTRHD1,PTTG1, PTTG1IP, PTTG4P, PURG, PVR, PVRL2, PVRL4, PWRN1, PXDN, PXMP2,PYCARD, PYCR1, PYGB, PYROXD2, PYY, QARS, QDPR, QPCTL, QPRT, QRSL1P3,QTRT1, R3HDML, RAB11B, RAB11FIP1P1, RAB11FIP3, RAB17, RAB19, RAB1B,RAB1C, RAB25, RAB26, RAB27B, RAB33A, RAB34, RAB36, RAB37, RAB38, RAB3A,RAB3D, RAB3IL1, RAB40C, RAB43, RAB43P1, RAB6B, RABEP2, RABGGTA, RABL2A,RABL2B, RABL6, RAC3, RAD51, RAD54L2, RAD9A, RADIL, RAGE, RALGDS, RALY,RAMP1, RAMP2, RAMP2-AS1, RANBP1, RANBP10, RANBP17, RANBP3, RANGRF,RANP4, RANP8, RAP1AP, RAP1GAP, RAP1GAP2, RAPGEF1, RAPGEF3, RAPGEF4,RAPGEF4-AS1, RAPGEFL1, RAPSN, RARG, RARRES2, RASA3, RASA4CP, RASGRP2,RASGRP4, RASIP1, RASL10B, RASL11B, RASSF10, RASSF2, RASSF7, RASSF9,RAVER1, RBBP4P4, RBBP4P5, RBBP9, RBM10, RBM14- RBM4, RBM24, RBM33,RBM44, RBM46, RBM5, RBM6, RBMS1, RBMS1P1, RBMS2P1, RBMS3, RBMX2P5, RBP1,RBP2, RBP3, RBP5, RBPMS2, RCADH5, RCC1, RCC2, RCCD1, RCE1, RCN3, RCOR2,RD3, RDH12, RDH16, RDM1, REC8, RECQL4, RECQL5, REEP1, REEP2, REEP6,REG4, RELN, REM2, RENBP, RERE, RERG, RERG-IT1, RESP18, RET, REXO1, RFNG,RFPL1, RFPL2, RFTN2, RFWD2P1, RFX2, RFX4, RFX5, RFXANK, RGAG4, RGL2,RGL3, RGMA, RGPD2, RGPD6, RGS12, RGS14, RGS3, RGS6, RGS8, RHBDF1,RHBDL1, RHBDL2, RHBG, RHOA-IT1, RHOB, RHOBTB2, RHOC, RHOF, RHOH,RHOT1P2, RHOT2, RHOU, RHOV, RHOXF1, RHPN1, RHPN1-AS1, RHPN2, RIMBP2,RIMS1, RIMS3, RIMS4, RIPK4, RIT2, RLBP1, RLTPR, RMI2, RMST, RNA5SP115,RNA5SP174, RNA5SP195, RNA5SP210, RNA5SP260, RNA5SP284, RNA5SP298,RNA5SP316, RNA5SP320, RNA5SP340, RNA5SP364, RNA5SP37, RNA5SP39,RNA5SP395, RNA5SP434, RNA5SP440, RNA5SP442, RNA5SP48, RNA5SP482,RNA5SP493, RNA5SP495, RNA5SP507, RNA5SP78, RNA5SP82, RNase_MRP, RNASE10,RNASE4, RNASEH1P1, RNASEH2A, RNASEH2B-AS1, RND1, RND2, RND3, RNF112,RNF113B, RNF122, RNF144, RNF144A, RNF144A-AS1, RNF150, RNF157, RNF165,RNF17, RNF182, RNF207, RNF208, RNF215, RNF220, RNF224, RNF24, RNF26,RNF2P1, RNF31, RNF43, RNF44, RNF6P1, RNF7P1, RNU12, RNU4-2, RNU5D-1,RNU5E-8P, RNU5F-1, RNU5F- 4P, RNU6-30, RNU6-48, RNU6-50, RNU6-60,RNU7-16P, RNU7-40P, RNU7-49P, RNU7-57P, RNY1P4, RNY4P20, ROBO3, ROGDI,ROMO1, ROR2, ROS1, RP1- 102G20.4, RP1-102H19.6, RP11-1000B6.2,RP11-1000B6.3, RP11-1000B6.5, RP11- 1007J8.1, RP11-1008C21.2,RP11-100G15.7, RP11-100N21.1, RP11-1012A1.4, RP11-101C21.1,RP11-101E14.2, RP11-1023L17.2, RP11-1024P17.1, RP11- 102M11.2,RP11-1035H13.3, RP11-1038A11.1, RP11-1038A11.3, RP11-103G8.1,RP11-103G8.2, RP11-103H7.5, RP11-103J17.2, RP11-104D21.3, RP11-104E19.1,RP11-104H15.8, RP11-104H15.9, RP11-104N10.1, RP11-1055B8.4, RP11-1055B8.8, RP11-1058N17.1, RP11-105C19.2, RP11-106A1.2, RP11-106A1.3,RP11- 106E15.1, RP11-1072C15.1, RP11-1072C15.4, RP11-107F6.3,RP11-1081M5.1, RP11-1082L8.1, RP11-1084I9.2, RP11-1085N6.5,RP11-108E14.1, RP11-108K14.4, RP11-108L7.4, RP11-108L7.7, RP11-108M12.3,RP11-1099M24.8, RP11-109D20.1, RP11-109I13.2, RP11-109L13.1,RP11-109N23.4, RP11-109P14.9, RP11-10A14.5, RP11-10J21.5, RP11-10L12.2,RP11-10N23.5, RP11-10O17.3, RP11-1100L3.8, RP11-110G21.1, RP11-110L15.2,RP11-1112C15.2, RP11-1114A5.4, RP11-111F5.2, RP11-111G23.1,RP11-111H3.1, RP11-111I12.1, RP11-112J1.3, RP11-112N23.1,RP11-1136G11.8, RP11-113I24.1, RP11-1143G9.2, RP11-1143G9.4, RP11-114G22.1, RP11-114H7.1, RP11-1151B14.4, RP11-115C9.2, RP11-115K3.1,RP11- 115K3.2, RP11-115P21.1, RP11-1167A19.6, RP11-116K4.1,RP11-118B22.4, RP11- 118E18.2, RP11-1191J2.2, RP11-119F19.4,RP11-119F7.3, RP11-119F7.4, RP11- 119F7.5, RP11-119H12.4, RP11-11M20.2,RP11-11N5.1, RP11-11N9.4, RP11- 120B7.1, RP11-120M18.5, RP11-1212A22.1,RP11-1212A22.4, RP11-121G22.3, RP11-121L11.1, RP11-1220K2.2,RP11-1223D19.1, RP11-122C5.3, RP11- 122D10.1, RP11-122K13.12,RP11-122K13.7, RP11-123K19.1, RP11-123K19.2, RP11-124L5.7,RP11-124N14.3, RP11-124N14.4, RP11-124N19.3, RP11-124N2.1,RP11-124O11.2, RP11-1258F18.1, RP11-126K1.6, RP11-126L15.4,RP11-126O1.5, RP11-1277A3.2, RP11-127I20.7, RP11-128P10.1,RP11-129B22.1, RP11-129I19.2, RP11-129M6.1, RP11-12J10.3, RP11-12M5.3,RP11-130F10.1, RP11-1319K7.1, RP11-131L23.1, RP11-131N11.4,RP11-132A1.3, RP11-132G10.2, RP11-132N15.1, RP11-133K1.7,RP11-133N21.10, RP11-134K1.2, RP11-134P9.3, RP11-135A24.4, RP11-135J2.4,RP11-1365D11.1, RP11-136K7.1, RP11-136K7.3, RP11-1376P16.1,RP11-1376P16.2, RP11-1379J22.3, RP11-1379J22.5, RP11-138B4.1,RP11-138H8.6, RP11-1391J7.1, RP11-1396O13.1, RP11-1396O13.2,RP11-139F4.1, RP11-13A1.1, RP11-13K12.1, RP11-13L2.4, RP11-1415C14.3,RP11-142A5.1, RP11-142C4.5, RP11-142C4.6, RP11-142G1.2, RP11-142I20.1,RP11-143K11.1, RP11-143K11.5, RP11-143M1.2, RP11-144G6.9,RP11-144O23.20, RP11-146D12.2, RP11-146F11.1, RP11-147L13.2,RP11-148G20.1, RP11-148K1.12, RP11-148L24.1, RP11- 148O21.3,RP11-148O21.4, RP11-149F8.9, RP11-149I23.3, RP11-14C22.4, RP11-150O12.1, RP11-152F13.3, RP11-152F13.7, RP11-152L20.2, RP11-153K11.3,RP11-153K16.1, RP11-154D17.1, RP11-154D3.1, RP11-154D6.1, RP11-154J22.1,RP11-156F12.1, RP11-156G14.6, RP11-156P1.3, RP11-157J24.1, RP11-157L3.5,RP11-158J3.2, RP11-158L12.2, RP11-158M2.5, RP11-159D12.5, RP11-159F24.5,RP11-159H22.2, RP11-159K7.2, RP11-159M11.2, RP11-159N11.3, RP11-15B17.1,RP11-15B17.2, RP11-15N24.4, RP11-160A10.2, RP11-161H23.8, RP11-161M6.2,RP11-162J8.2, RP11-163N6.2, RP11-164C12.1, RP11-164H5.1, RP11-165F24.3,RP11-165J3.6, RP11-165O3.2, RP11-165P7.1, RP11-166O4.5, RP11-167H9.5,RP11-167N4.2, RP11-167N4.4, RP11-168G16.2, RP11-168K11.2, RP11-168K11.3,RP11-168O16.1, RP11-168O16.2, RP11-169D4.2, RP11-16E12.1, RP11-16E12.2,RP11-16E23.3, RP11-16F15.2, RP11-16L21.7, RP11-170N11.1, RP11-171G2.1,RP11-173A16.1, RP11-173A16.2, RP11-173D14.3, RP11-173D9.3,RP11-173G21.1, RP11-173M1.8, RP11-174M13.2, RP11-174O3.3, RP11-175D17.3,RP11-175I17.4, RP11-175P13.2, RP11-176F3.7, RP11-176H8.1, RP11-177B4.1,RP11-177F11.1, RP11-177N22.2, RP11-178D16.1, RP11-178L8.3, RP11-17A4.2,RP11-17G12.2, RP11-17G12.3, RP11-17M24.2, RP11-180A12.4, RP11-180I22.2,RP11-180P8.3, RP11-181B18.1, RP11-181G12.2, RP11-181K12.2,RP11-182I10.3, RP11-182J1.12, RP11-182J1.16, RP11-182J1.5,RP11-182L21.2, RP11-183E9.3, RP11-183G22.1, RP11-183G22.3,RP11-187C18.3, RP11-187O7.1, RP11-187O7.3, RP11-188C12.2, RP11-188C12.3,RP11-18D7.2, RP11-18I14.7, RP11-190P13.1, RP11-191G24.1, RP11-192C21.1,RP11-192H23.7, RP11-195E2.1, RP11-196G11.1, RP11-196H14.4, RP11-198M6.2,RP11-199F11.2, RP11-19O2.2, RP11-1C8.5, RP11-1E6.1, RP11- 1H8.3,RP11-1L12.3, RP11-1O10.1, RP11-203I2.1, RP11-203M5.4, RP11-204K16.1,RP11-204L24.2, RP11-206L10.1, RP11-206L10.3, RP11-206L10.8,RP11-206P5.2, RP11-209A2.1, RP11-209D14.2, RP11-20B24.4, RP11-20B24.7,RP11-20D14.6, RP11-20G13.1, RP11-20G13.2, RP11-20G13.3, RP1-120G22.11,RP11-20I23.1, RP11-20I23.11, RP11-20I23.6, RP11-20I23.8, RP11-20L24.1,RP11-20P5.2, RP11- 210M15.2, RP11-211A18.2, RP11-212D19.5,RP11-212F11.1, RP11-212I21.4, RP11-213G2.5, RP11-214C8.2, RP11-214D15.2,RP11-214O1.2, RP11-215D10.1, RP11-215E13.1, RP11-215P8.1, RP11-215P8.3,RP11-216C10.1, RP11-216M21.1, RP11-216N14.7, RP11-216N14.8,RP11-216N14.9, RP11-218C14.5, RP11- 218E20.6, RP11-219B4.3,RP11-219B4.7, RP11-219G17.4, RP11-21A7A.2, RP11- 21A7A.3, RP11-21A7A.4,RP11-21B21.4, RP1-121G13.3, RP11-21G15.1, RP11- 21L23.2, RP11-21L23.4,RP11-21M24.2, RP11-21M24.3, RP11-21N7.2, RP11- 223I10.1, RP11-224O19.2,RP11-224O19.4, RP11-225B17.1, RP11-225H22.4, RP11-225H22.5,RP11-225N10.1, RP11-227G15.2, RP11-227G15.6, RP11- 227G15.8,RP11-227H15.5, RP11-227J5.3, RP11-229C3.2, RP11-229P13.2, RP11-229P13.22, RP11-229P13.23, RP11-22A3.2, RP11-22B23.1, RP11-22M7.2, RP1-122O8.7, RP1-122P22.2, RP11-22P6.2, RP11-230B22.1, RP11-231C14.3, RP11-231C14.4, RP11-233G1.4, RP11-234B24.5, RP11-235E17.4, RP11-235E17.6,RP11- 238K6.1, RP11-239E10.2, RP11-239L20.5, RP11-23J18.1, RP11-23J9.5,RP11- 23P13.4, RP11-240L7.4, RP11-243M5.1, RP11-244C20.1, RP11-244F12.3,RP11- 244N9.4, RP11-244O19.1, RP11-245J9.4, RP11-247A12.1,RP11-247A12.2, RP11- 247I13.7, RP11-248B10.2, RP11-24M17.3,RP11-24M17.7, RP11-250B2.3, RP11- 250B2.5, RP11-251A15.4, RP11-251G23.2,RP11-252E2.1, RP11-252K23.1, RP11- 252K23.2, RP11-255A11.21,RP11-255G12.2, RP11-258B16.1, RP11-259G18.2, RP11-259G18.3,RP11-259O2.1, RP11-259P1.1, RP11-25B7.1, RP11-25H12.1, RP1- 125I3.2,RP11-25K19.1, RP11-260M19.2, RP11-261N11.8, RP11-261P9.4, RP11-262H14.1, RP11-262H14.10, RP11-262H14.11, RP11-262I2.2, RP11-263K19.4,RP11-263K19.6, RP11-264B14.1, RP11-264B17.4, RP11-264B17.5,RP11-264L1.4, RP11-264P13.2, RP11-265B8.4, RP11-265D17.2, RP11-266K4.1,RP11-266K4.9, RP11-266L9.1, RP11-266L9.2, RP11-266L9.3, RP11-266L9.4,RP11-266L9.5, RP11-266N13.2, RP11-266O8.1, RP11-267D19.2, RP11-267J23.4,RP11-267M23.4, RP11-268I9.1, RP11-268I9.3, RP11-268P4.4, RP11-269C23.3,RP11-269C4.2, RP11-269G24.4, RP11-26H16.1, RP11-26J3.1, RP11-26M5.2,RP11-271O3.1, RP11- 272D12.2, RP11-272J7.4, RP11-273B20.1,RP11-273G15.2, RP11-274B21.2, RP11- 274B21.3, RP11-274B21.4,RP11-274B21.5, RP11-274J15.2, RP11-274J7.3, RP11- 274K13.2,RP11-276A18.2, RP11-276H19.2, RP11-276M12.1, RP11-277B15.1,RP11-278L15.2, RP11-278L15.6, RP11-279F6.1, RP11-279F6.2, RP11-279F6.3,RP11-279N8.3, RP1-127H14.3, RP11-281P23.2, 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RP11-697E2.6, RP11-697E22.2,RP11-697M17.1, RP11-69D4.3, RP11-69D4.5, RP11-69I8.3, RP11- 69M1.3,RP11-6J21.2, RP11-701H24.4, RP11-703I16.1, RP11-704M14.1, RP11-705C15.2, RP11-705C15.3, RP11-705C15.4, RP11-705O24.1, RP11-706O15.1,RP11-706O15.3, RP11-707G14.3, RP11-707G14.7, RP11-708L7.6,RP11-709A23.2, RP11-70C1.3, RP11-70F11.2, RP11-711G10.1, RP11-711M9.1,RP11-712L6.7, RP11-713C5.1, RP11-714L20.1, RP11-715J22.2, RP11-715J22.3,RP11-715J22.4, RP11-715J22.6, RP11-717D12.1, RP11-718B12.2,RP11-718B12.3, RP11-718O11.1, RP11-719K4.1, RP11-719K4.2, RP11-71E19.1,RP11-71H17.7, RP11-723C11.2, RP11-723O4.2, RP11-723O4.9, RP11-728F11.4,RP1-172N19.3, RP11-731J8.1, RP11-731J8.2, RP11-732A19.5, RP11-732A19.6,RP11-732A19.8, RP11-732A19.9, RP11-734C14.10, RP11-736N17.4,RP11-739G5.1, RP11-744H18.1, RP11-744I24.3, RP11-745A24.2,RP11-745C15.2, RP11-745O10.2, RP11-747H12.6, RP11- 748L13.1,RP11-74C13.4, RP11-74H8.1, RP11-74K19.1, RP11-753D20.1, RP11- 753H16.5,RP11-754B17.1, RP11-755B10.2, RP11-755F10.1, RP11-757C15.4,RP11-757F18.3, RP11-757G1.5, RP11-758C21.1, RP11-75A9.1, RP11-75A9.3,RP11-75C9.1, RP11-75N4.2, RP11-760D2.10, RP11-760N9.1, RP11-761E20.1,RP11-762B21.5, RP11-763B22.9, RP11-764K9.1, RP11-764K9.2, RP11-764K9.3,RP11-767I20.1, RP11-767L7.1, RP11-768F21.1, RP11-769O8.3, RP11-76C10.5,RP11-76E16.2, RP11-76H14.2, RP11-76K13.3, RP11-770G2.5, RP11-771F20.1,RP11-773H22.1, RP11-779O18.3, RP11-77H9.2, RP11-77H9.5, RP11-77P16.4,RP11-780K2.1, RP11-781P6.1, RP11-783K16.13, RP11-783K16.5, RP11-785H5.1,RP11-785H5.2, RP11-788H18.1, RP11-78F17.1, RP11-790G19.2, RP11-791G16.4,RP11-793H13.9, RP11-795F19.1, RP11-795F19.5, RP11-796E2.4,RP11-797A18.3, RP11-797E24.3, RP11-797M17.1, RP11-798G7.5, RP11-79C6.1,RP11-79H23.3, RP11-800A3.7, RP11-802E16.3, RP11-803B1.5, RP11-806L2.2,RP11-807H7.1, RP11-809N8.5, RP11-809O17.1, RP11-80A15.1, RP11-80B9.1,RP11-80H18.3, RP11-815J21.2, RP11-815J4.7, RP11-817O13.2, RP11-817O13.8,RP11-81H3.2, RP11-81K13.1, RP11-81K2.1, RP11-820I16.1, RP11-823P9.1,RP11-823P9.3, RP11- 826N14.4, RP11-829H16.2, RP11-829H16.3,RP11-82C23.2, RP11-82K18.2, RP11- 82L18.2, RP11-82L18.4, RP11-82L7.4,RP1-182O16.2, RP11-82O19.1, RP11- 831A10.1, RP11-834C11.11,RP11-834C11.3, RP11-834C11, 4, RP11-834C11.7, RP11-839D17.2,RP11-839G9.1, RP11-83A24.1, RP11-83M16.3, RP11-83M16.4, RP11-83M16.5,RP11-83M16.6, RP11-841C19.6, RP11-843B15.2, RP11-844P9.2, RP11-845C23.3,RP11-846F4.12, RP11-848D3.4, RP11-848G14.2, RP11-848G14.5, RP11-848P1.4,RP11-848P1.5, RP11-849F2.5, RP11-849H4.4, RP11-849I19.1, RP11-84A14.5,RP1-184J9.2, RP11-84O12.2, RP11-84P7.2, RP11-854K16.1, RP11- 855A2.3,RP11-855A2.5, RP11-855O10.2, RP11-856F16.2, RP11-85B7.2, RP11- 862G15.2,RP11-862L9.3, RP11-863K10.2, RP11-863P13.4, RP11-867G2.8, RP11-867G23.2, RP11-867G23.3, RP11-867G23.4, RP11-867G23.8, RP11-86H7.1,RP11- 86H7.7, RP11-871F6.2, RP11-875O11.1, RP11-876N24.2, RP1-187B23.1,RP11- 87C12.5, RP11-87G24.3, RP11-87H9.2, RP11-87H9.3, RP11-87N24.2,RP11- 883G14.2, RP11-883G14.3, RP11-885B4.1, RP11-889L3.4, RP11-88H10.2,RP11- 88H9.1, RP11-88H9.2, RP11-88I18.4, RP11-88I21.1, RP11-88K11.1,RP11- 88M19.3, RP11-893F2.5, RP11-903H12.3, RP11-907D1.2, RP11-909N17.3,RP11- 90B22.2, RP11-90B9.2, RP11-90D4.1, RP11-90D4.2, RP11-90H3.2,RP11-90K6.1, RP11-90M11.1, RP11-91A18.4, RP11-91A18.5, RP11-91I20.3,RP11-91K8.2, RP11- 91K9.1, RP11-91N2.3, RP11-91P24.5, RP11-91P24.7,RP11-923I11.4, RP11- 923I11.5, RP11-923I11.6, RP11-923I11.7,RP11-930O11.1, RP11-930P14.1, RP11- 930P14.2, RP11-939C17.2,RP1-193H18.2, RP11-93I21.3, RP11-93K22.11, RP11- 93O14.2, RP11-944L7.2,RP11-944L7.4, RP11-945A13.1, RP11-945C19.1, RP11- 945C19.4,RP11-94C24.8, RP11-94M14.2, RP11-958N24.1, RP11-958N24.2, RP11- 95M15.1,RP11-95M15.2, RP11-95O2.1, RP11-95O2.5, RP11-95P13.1, RP11- 961A15.1,RP11-96C23.10, RP11-96C23.7, RP11-96C23.8, RP11-96D1.5, RP11- 96G10.1,RP11-96H17.2, RP11-96K19.4, RP11-96L7.2, RP11-972L6.2, RP11- 973N13.2,RP11-974F13.6, RP11-977G19.5, RP11-97O12.2, RP1-197O17.2, RP11- 981G7.3,RP11-981P6.1, RP11-986G18.1, RP11-989F5.3, RP11-98G7.1, RP11- 998D10.2,RP11-998D10.7, RP11-99A14.1, RP1-199J3.5, RP11-9M16.2, RP1- 200G19.1,RP1-203P18.1, RP1-206D15.5, RP1-228H13.1, RP1-234P15.4, RP1- 240B8.3,RP1-240K6.3, RP1-241P17.1, RP1-241P17.3, RP1-249I4.2, RP1-257A7.4,RP1-261D10.1, RP1-265C24.8, RP1-266L20.4, RP1-266L20.9, RP1-269M15.3,RP1- 272J12.1, RP1-272L16.1, RP1-273P12.3, RP1-279N11.1, RP1-283E3.4,RP1- 288H2.2, RP1-288L1.4, RP1-288L1.5, RP1-292L20.1, RP1-295F6.2,RP1-302D9.3, RP1-304B14.3, RP1-308E4.1, RP13-100B2.4, RP1-310O13.12,RP1-310O13.7, RP13-131K19.2, RP13-140E4.1, RP13-15E13.1, RP13-15M17.1,RP13-192B19.2, RP13-221M14.5, RP13-225O21.2, RP13-25N22.1, RP13-262C2.1,RP13-279N23.2, RP1-32I10.10, RP13-36G14.3, RP13-371D18.2, RP13-379L11.2,RP13-395E19.2, RP13-39P12.2, RP13-39P12.3, RP13-401N8.1, RP13-439H18.7,RP13-467H17.1, RP13-494C23.1, RP1-34B20.4, RP13-516M14.4, RP13-608F4.4,RP13-638C3.2, RP13-726E6.1, RP13-726E6.2, RP1-37C10.3, RP13-7D7.1,RP13-884E18.2, RP13- 890H12.2, RP13-895J2.7, RP13-93L13.2,RP13-977J11.2, RP13-98N21.2, RP13- 991F5.2, RP13-991F5.4, RP1-40E16.11,RP1-40E16.8, RP1-4G17.2, RP1-56J10.8, RP1-59D14.1, RP1-59D14.6,RP1-5O6.6, RP1-60O19.2, RP1-63G5.5, RP1-63G5.7, RP1-64K7.4, RP1-67A8.3,RP1-67M12.2, RP1-85F18.6, RP1-89D411, RP1- 90G24.10, RP1-90G24.6,RP1-90L6.2, RP1-97J1.2, RP3-324N14.2, RP3-329E20.2, RP3-330M21.5,RP3-336K20_B.2, RP3-337H4.8, RP3-354N19.3, RP3-370M22.8, RP3-377D14.1,RP3-382I10.3, RP3-399L15.3, RP3-404F18.5, RP3-405J10.4, RP3- 406P24.3,RP3-410B11.1, RP3-412A9.10, RP3-414A15.11, RP3-415N12.1, RP3- 423B22.5,RP3-428L16.1, RP3-434P1.6, RP3-439F8.1, RP3-441A12.1, RP3- 449O17.1,RP3-462E2.3, RP3-465N24.5, RP3-467K16.4, RP3-468B3.2, RP3- 470B24.5,RP3-473L9.3, RP3-476K8.3, RP3-476K8.4, RP3-477O4.5, RP3- 481A17.1,RP3-497J21.1, RP3-508I15.10, RP3-508I15.14, RP3-510D11.2, RP3- 510L9.1,RP3-510O8.4, RP3-511B24.5, RP3-512B11.3, RP3-514A23.2, RP3- 518E13.2,RP3-522P13.3, RP3-523C21.1, RP3-523K23.2, RP3-525N10.2, RP4- 530I15.6,RP4-533D7.4, RP4-533D7.5, RP4-534N18.2, RP4-536B24.4, RP4- 537K23.4,RP4-539M6.14, RP4-541C22.5, RP4-545K15.3, RP4-545K15.5, RP4- 545L17.7,RP4-549L20.2, RP4-555D20.2, RP4-555L14.4, RP4-560B9.1, RP4- 562J12.2,RP4-566D2.1, RP4-575N6.2, RP4-583P15.10, RP4-583P15.11, RP4- 584D14.6,RP4-584D14.7, RP4-591N18.2, RP4-593C16.3, RP4-601K24.1, RP4- 601P9.2,RP4-603I14.3, RP4-604G5.1, RP4-612J11.1, RP4-620F22.3, RP4-622L5.7,RP4-633O19_A.1, RP4-635E18.7, RP4-639F20.1, RP4-639F20.3, RP4-647C14.2,RP4-647C14.5, RP4-650F12.2, RP4-655J12.3, RP4-663N10.1, RP4-665J23.2,RP4- 669L17.10, RP4-669P10.16, RP4-673D20.3, RP4-673D20.4, RP4-676L2.1,RP4- 686C3.7, RP4-694B14.4, RP4-697K14.7, RP4-701O16.5, RP4-706L14.2,RP4- 710M16.2, RP4-724E16.2, RP4-728D4.2, RP4-730K3.3, RP4-734P14.4,RP4- 738P11.4, RP4-742J24.2, RP4-745E8.2, RP4-747G18.5, RP4-753P9.3,RP4- 756H11.3, RP4-758J18.10, RP4-758J18.7, RP4-758J18.8, RP4-758J18.9,RP4- 763G1.1, RP4-765C7.1, RP4-773A18.4, RP4-773N10.5, RP4-777D9.2, RP4-781B1.2, RP4-781K5.4, RP4-782L23.2, RP4-784A16.2, RP4-791K14.2, RP4-792G4.2, RP4-796I8.1, RP4-798A17.5, RP4-798C17.5, RP4-799P18.2, RP4-799P18.5, RP4-800G7.2, RP4-811H24.6, RP5-1024C24.1, RP5-1025A1.2, RP5-1039K5.13, RP5-1041C10.3, RP5-1052I5.1, RP5-1061H20.3, RP5-1061H20.4,RP5- 1063M23.1, RP5-1068B5.3, RP5-1071N3.1, RP5-1086D14.3,105-1091E12.1, RP5- 1096D14.6, RP5-1099D15.1, RP5-1101C3.1,RP5-1103B4.3, RP5-1107A17.4, RP5- 1119A7.11, RP5-1119D9.4, RP5-1142A6.3,RP5-1142A6.9, RP5-1172N10.2, RP5- 1177E19.2, RP5-1184F4.5,RP5-1187M17.10, RP5-1189B24.4, RP5-827C21.1, RP5- 837I24.1,RP5-837I24.6, RP5-839B4.8, RP5-854E16.2, RP5-864K19.4, RP5- 875H3.2,RP5-875O13.1, RP5-881L22.4, RP5-881L22.5, RP5-882C2.2, RP5- 884C9.2,RP5-890O3.3, RP5-894D12.3, RP5-894H24.2, RP5-896L10.1, RP5- 901A4.1,RP5-902P8.10, RP5-902P8.12, RP5-906A24.2, RP5-914M6.1, RP5- 914P20.5,RP5-915N17.3, RP5-928E24.2, RP5-942I16.1, RP5-955M13.3, RP5- 955M13.4,RP5-968J1.1, RP5-968P14.2, RP5-977B1.10, RP5-977B1.11, RP5- 982E9.1,RP5-991G20.1, RP5-997D24.3, RP5-998N21.7, RP6-105D16.1, RP6- 159A1.2,RP6-170F5.2, RP6-239D12.1, RP6-24A23.3, RP6-24A23.7, RP6-33F8.1,RP6-65G23.3, RP9P, RPGRIP1, RPL12P33, RPL12P8, RPL13AP20, RPL17P25,RPL18AP7, RPL18P13, RPL19P12, RPL21P116, RPL21P119, RPL21P120,RPL21P122, RPL21P132, RPL21P2, RPL21P4, RPL21P54, RPL23AP10, RPL23AP80,RPL31P52, RPL32P3, RPL32P34, RPL34P27, RPL35AP31, RPL35AP33, RPL36P4,RPL37P1, RPL39L, RPL3P3, RPL3P9, RPL5P30, RPL6P25, RPL6P30, RPL7AP11,RPL7AP58, RPL7AP73, RPL7L1P11, RPL7P14, RPL7P3, RPL7P47, RPL9P18,RPL9P2, RPL9P32, RPL9P8, RPLP0P2, RPRM, RPRML, RPS12P28, RPS15AP10,RPS15AP16, RPS15AP18, RPS15AP5, RPS15P5, RPS16P8, RPS19P3, RPS20P15,RPS20P33, RPS23P6, RPS26P11, RPS26P31, RPS26P49, RPS26P55, RPS26P6,RPS27P12, RPS27P16, RPS27P25, RPS2P1, RPS2P5, RPS2P7, RPS3AP49, RPS3P6,RPS5P3, RPS6KA2, RPS6KA2-IT1, RPS6KB2, RPS6KL1, RPS7P14, RPS9P1,RPSAP14, RPSAP43, RPSAP52, RPSAP8, RPSAP9, RPTOR, RPUSD1, RRAS, RRM2,RRM2P3, RRN3P3, RRP7B, RSF1-IT1, RSL24D1P2, RSL24D1P5, RSPO3, RSPO4,RTEL1P1, RTKN, RTKN2, RTL1, RTN2, RTN4R, RTN4RL1, RTN4RL2, RUNDC3A,RWDD4P1, RXFP4, RYK, RYKP1, RYR1, S100A1, S100A10, S100A13, S100A14,S100A16, S100A4, S100P, S100Z, S1PR2, S1PR3, S1PR4, SAC3D1, SAE1, SALL1,SALL3, SALL4P5, SAMD10, SAMD14, SAMD15, SAMD4A, SAMD5, SAMHD1, SAMM50,SAP30BP, SAPCD2, SARDH, SARM1, SARS2, SASH1, SBF1P1, SBK1, SBK2, SBSPON,SC65, SCAF1, SCAMP4, SCAMP5, SCAP, SCARA3, SCARB1, SCARF2, SCARNA11,SCARNA16, SCARNA18, SCARNA2, SCARNA24, SCCPDH, SCEL, SCHIP1, SCML4,SCN11A, SCN1A, SCN2B, SCN3A, SCN4B, SCN5A, SCN7A, SCN9A, SCNN1D, SCNN1G,SCRG1, SCRN2, SCT, SCUBE1, SCUBE2, SCUBE3, SDC1, SDC3, SDC4, SDC4P,SDHAP3, SDHDP2, SDHDP6, SDK1, SDK2, SDR9C7, SEC14L1, SEC14L4, SEC14L5,SEC14L6, SEC1P, SEC31B, SEC61A2, SELENBP1, SELI, SELL, SELV, SEMA3A,SEMA3B, SEMA3C, SEMA3D, SEMA3F, SEMA3G, SEMA4C, SEMA4D, SEMA4F, SEMA4G,SEMA5B, SEMA6B, SEMA6C, SEMA7A, SENP7, SEPHS1P1, SEPN1, SEPX1, SERHL2,SERINC2, SERINC5, SERPINA1, SERPINA10, SERPINA11, SERPINB9, SERPIND1,SERPINF1, SERPINF2, SERPING1, SERPINH1, SERPIN11, SERPINI2, SERTM1, SET,SETD1A, SETDB1, SETP17, SETP4, SETP6, SEZ6, SEZ6L, SEZ6L2, SF3A2, SFRP1,SFRP2, SFRP5, SFRS6, SFTA3, SFTPB, SFTPD, SGCD, SGCZ, SGK494, SGSH,SGTA, SH2B1, SH2B2, SH2D3A, SH2D3C, SH2D7, SH3BP1, SH3BP2, SH3BP4,SH3BP5, SH3D21, SH3GL1P3, SH3GLB2, SH3KBP1, SH3PXD2B, SH3RF1, SH3RF3,SH3RF3-AS1, SHANK1, SHANK2, SHANK3, SHARPIN, SHBG, SHC1P1, SHC2, SHC3,SHC4, SHD, SHF, SHH, SHISA2, SHISA4, SHISA6, SHISA7, SHISA9, SHKBP1,SHOX2, SHPK, SHRM, SHROOM3, SHROOM4, SI, SIAH2-AS1, SIDT2, SIGIRR,SIGLEC15, SIGLEC6, SIK3-IT1, SIN3B, SIPA1, SIRPA, SIRPAP1, SIRT2, SIRT3,SIRT4, SIT1, SIX5, SKA1, SKA3, SKIDA1, SKOR1, SKOR2, SLC10A1, SLC12A1,SLC12A2, SLC12A3, SLC12A4, SLC12A5, SLC12A7, SLC12A9, SLC13A3, SLC13A5,SLC14A1, SLC15A1, SLC15A4, SLC16A1, SLC16A11, SLC16A13, SLC16A3,SLC16A5, SLC16A7, SLC16A8, SLC17A1, SLC17A3, SLC17A7, SLC17A8, SLC17A9,SLC18A1, SLC18A3, SLC18B1, SLC19A1, SLC19A3, SLC1A3, SLC1A5, SLC1A6,SLC1A7, SLC22A11, SLC22A14, SLC22A16, SLC22A18, SLC22A18AS, SLC22A20,SLC22A23, SLC22A3, SLC22A4, SLC22A7, SLC22A8, SLC23A1, SLC24A3, SLC24A6,SLC25A1, SLC25A14P1, SLC25A15, SLC25A18, SLC25A1P1, SLC25A20, SLC25A23,SLC25A29, SLC25A33, SLC25A38, SLC25A41, SLC25A5, SLC25A5P2, SLC25A5P3,SLC25A6P2, SLC26A1, SLC26A10, SLC26A11, SLC26A4, SLC26A4-AS1, SLC26A6,SLC26A8, SLC27A1, SLC27A3, SLC29A1, SLC29A2, SLC29A3, SLC29A4,SLC29A4P1, SLC2A1, SLC2A14, SLC2A1-AS1, SLC2A3, SLC2A4, SLC2A4RG,SLC2A8, SLC30A10, SLC30A3, SLC32A1, SLC34A3, SLC35C2, SLC35D2, SLC35E3,SLC35E4, SLC35F1, SLC35F4, SLC36A1, SLC37A4, SLC38A1, SLC38A11, SLC38A3,SLC38A5, SLC38A7, SLC38A9, SLC39A13, SLC39A2, SLC39A5, SLC41A3, SLC43A1,SLC43A3, SLC44A2, SLC44A3, SLC44A5, SLC45A1, SLC46A2, SLC4A1, SLC4A11,SLC4A2, SLC4A3, SLC52A1, SLC5A11, SLC5A12, SLC5A6, SLC5A7, SLC5A8,SLC5A9, SLC6A1, SLC6A11, SLC6A12, SLC6A15, SLC6A16, SLC6A18, SLC6A19,SLC6A2, SLC6A3, SLC6A4, SLC6A5, SLC6A8, SLC7A10, SLC7A11-AS1, SLC7A14,SLC7A15P, SLC7A3, SLC7A4, SLC7A5P2, SLC7A7, SLC8A2, SLC9A2, SLC9A3,SLC9A3P2, SLC9A3R1, SLC9A5, SLC9A7, SLCO1B1, SLCO2A1, SLCO4C1, SLCO6A1,SLFN13, SLIT1, SLIT2, SLIT3, SLITRK1, SLITRK2, SLITRK3, SLITRK4,SLITRK5, SLMO1, SLN, SMAD5-AS1, SMAD6, SMAD9-AS1, SMAGP, SMARCA2,SMARCA4, SMARCA5-AS1, SMARCAL1, SMARCB1, SMARCC1, SMARCE1P1, SMARCE1P2,SMC2, SMCR2, SMCR5, SMG5, SMG6, SMIM1, SMN2, SMO, SMOC1, SMOC2, SMPD3,SMPD4, SMPDL3B, SMTN, SMTNL2, SMUG1, SMYD2, SMYD3, SNAI3, SNAP47-AS1,SNAPC3, SNAPC4, SNCAIP, SNCG, SNED1, SNHG11, SNN, SNORA11, SNORA12,SNORA15, SNORA2, SNORA2A, SNORA30, SNORA31, SNORA34, SNORA42, SNORA46,SNORA53, SNORA66, SNORA67, SNORA7, SNORA70, SNORA70G, SNORA71B, SNORA75,SNORA77, SNORA79, SNORA80B, SNORA9, SNORD101, SNORD123, SNORD12B,SNORD15A, SNORD23, SNORD46, SNORD56, SNORD60, SNORD7, SNORD70, SNORD83A,SNORD91A, SNORD96B, snoU13, SNRPD2P1, SNRPGP9, SNTA1, SNTG2, SNX15,SNX26, SNX30, SNX32, SNX33, SNX8, SOAT2, SOCS2P2, SOGA1, SOHLH1, SORBS1,SORBS3, SORCS1, SORCS2, SORCS3, SOS1-IT1, SOSTDC1, SOWAHD, SOX1, SOX10,SOX11, SOX12, SOX15, SOX17, SOX2, SOX21, SOX21-AS1, SOX3, SOX4, SOX8,SP3P, SP4, SP6, SP7, SPACA3, SPACA4, SPAG4, SPAG5, SPAG7, SPANXA2-OT1,SPARC, SPATA20, SPATA2L, SPATA8, SPATC1, SPATS1, SPATS2L, SPDEF, SPDYC,SPDYE2, SPDYE3, SPEG, SPG20OS, SPG7, SPHK2, SPIB, SPIN2A, SPIN4-AS1,SPINK1, SPINK5, SPINT1, SPINT2, SPIRE2, SPN, SPNS1, SPNS2, SPNS3,SPOCK1, SPOCK2, SPOCK3, SPON2, SPPL2B, SPRN, SPSB3, SPSB4, SPTAN1,SPTBN4, SPTLC3, SPTSSB, SQLE, SRC, SRCAP, SRCIN1, SRCRB4D, SRD5A2,SREBF2, SRGAP1, SRGAP3, SRL, SRP68P3, SRP72P1, SRPX, SRRM1P3, SRRM2,SRRM2-AS1, SRRM3, SRRM4, SRRM5, SRSF10P1, SSBP3, SSBP4, SSH3, SSPO, SST,SSTR1, SSTR2, SSTR5, ST13P2, ST13P20, ST3GAL2, ST3GAL3, ST6GAL1,ST6GALNAC1, ST6GALNAC3, ST6GALNAC4P1, ST6GALNAC5, ST8SIA1, ST8SIA2,ST8SIA4, ST8SIA5, STAB2, STAC, STAG3, STAG3L1, STAG3L2, STAG3L3,STARD10, STARD10- AS1, STARD3, STARD4-AS1, STARD5, STARD8, STARD9, STC1,STC2, STEAP1, STK10, STK11IP, STK16, STK17B, STK25, STK32C, STK36,STMN1, STMN2, STMN3, STMN4, STON1, STON2, STRA6, STRADB, STRN4, STX10,STX16-NPEPL1, STX1B, STXBP2, STYK1, SUCNR1, SUFU, SUGP1, SUGT1P2,SULT1B1, SULT1C2, SULT1C4, SULT1E1, SULT4A1, SUMO2P6, SUPT5H, SUPT6H,SUSD2, SUV39H1, SUV420H2, SV2B, SV2C, SVEP1, SVIL, SYCE1L, SYCE2, SYDE1,SYDE2, SYMPK, SYN2, SYN3, SYNCRIP, SYNDIG1L, SYNE1- AS1, SYNE3, SYNE4,SYNGAP1, SYNGR1, SYNJ2BP, SYNPO2L, SYNPR, SYNPR-AS1, SYPL2, SYT1, SYT10,SYT14L, SYT15, SYT17, SYT2, SYT3, SYT6, SYTL5, SZT2-AS1, TAAR1, TAB1,TAC1, TAC3, TAC4, TACC2, TACC3, TACR1, TACR3, TADA3, TAF13P2, TAF6,TAF6L, TAGLN, TAP2, TARBP1, TARBP2, TARDBPP2, TAS2R12, TAS2R18, TAS2R42,TAS2R5, TAS2R67P, TAX1BP3, TAZ, TBC1D10C, TBC1D13, TBC1D14, TBC1D16,TBC1D17, TBC1D25, TBC1D26, TBC1D3, TBC1D3C, TBC1D3F, TBC1D3G, TBC1D3P2,TBC1D7, TBCAP2, TBCB, TBKBP1, TBL1Y, TBX1, TBX10, TBX15, TBX2, TBX20,TBX22, TBX3, TBX4, TBX6, TCAP, TCEA2, TCEAL7, TCEAL8, TCEANC2, TCEB1P19,TCEB2, TCEB2P2, TCF2, TCF24, TCF25, TCF3, TCF7, TCF7L1, TCIRG1, TCN2,TCP10, TCTE1, TCTN1, TCTN2, TDG, TDH, TDO2, TEAD2, TEAD3, TECPR1, TECRL,TEKT2, TEKT3, TEKT4, TEKT5, TELO2, TEPP, TERF1P3, TERT, TET1, TET3,TEX15, TEX22, TEX264, TFAMP1, TFAP2A, TFAP2B, TFAP2E, TFB1M, TFDP2,TFF1, TFF2, TFF3, TFPI2, TFPT, TFR2, TGFB1, TGFB1I1, TGFB2, TGFBI,TGFBR2, TGIF2, TGM1, TGM3, TH, THA1P, THAP3, THAP7, THAP8, THBS1, THBS3,THBS4, THEG, THEM5, THG1L, THOC1, THOC5, THOP1, THRAP3P1, THRSP, THSD1,THSD4, THSD7A, THSD7B, THY1, TIA1, TIAM2, TICRR, TIGD5, TIMELESS,TIMM13, TIMM17B, TIMM22, TIMM8AP1, TIMM8BP2, TIMP3, TINAGL1, TJP2, TJP3,TK1, TLE1, TLE1P1, TLE2, TLE3, TLE6, TLR10, TLR5, TLX2, TLX3, TM4SF19,TM4SF19-AS1, TM4SF20, TM4SF4, TM4SF5, TM6SF1, TM6SF2, TM7SF2, TM9SF4,TMC3, TMC4, TMC6, TMC7, TMC8, TMED1, TMEFF1, TMEFF2, TMEM102, TMEM105,TMEM114, TMEM120A, TMEM120B, TMEM129, TMEM130, TMEM132A, TMEM132B,TMEM132D, TMEM132E, TMEM141, TMEM143, TMEM145, TMEM147, TMEM150A,TMEM150B, TMEM151A, TMEM151B, TMEM160, TMEM164, TMEM169, TMEM17,TMEM171, TMEM175, TMEM184B, TMEM190, TMEM191A, TMEM191C, TMEM198B,TMEM200C, TMEM201, TMEM202, TMEM204, TMEM206, TMEM213, TMEM217, TMEM222,TMEM229A, TMEM240, TMEM249, TMEM25, TMEM252, TMEM35, TMEM37, TMEM38A,TMEM41B, TMEM47, TMEM50A, TMEM52, TMEM53, TMEM56, TMEM59L, TMEM63A,TMEM63B, TMEM72, TMEM74, TMEM74B, TMEM79, TMEM8, TMEM80, TMEM86A,TMEM86B, TMEM88B, TMEM89, TMEM8A, TMEM91, TMEM92, TMEM98, TMIGD2,TMPRSS11CP, TMPRSS11GP, TMPRSS13, TMPRSS3, TMPRSS6, TMPRSS9, TMSB10,TMSB15A, TMSB15B, TMSB4XP1, TMTC1, TMTC4, TNC, TNFAIP2, TNFAIP8L1,TNFAIP8L3, TNFRSF10A, TNFRSF10D, TNFRSF18, TNFRSF25, TNFSF15, TNKS1BP1,TNNC2, TNNI1, TNNI3, TNNT1, TNNT2, TNNT3, TNP1, TNR, TNRC18, TNRC18P3,TNRC9, TOMM40L, TONSL, TOP1MT, TOP1P2, TOP2A, TOP3B, TOR1B, TOR2A,TOR4A, TOX2, TOX3, TP53, TP53AIP1, TP53I11, TP53I13, TP53I3, TP53INP1,TP63, TPBG, TPCN1, TPD52L1, TPGS1, TPI1P1, TPM1, TPM2, TPM3P4, TPM3P6,TPRN, TPRXL, TPSAB1, TPSD1, TPST2, TPTE2P1, TPX2, TRA2A, TRABD2A,TRABD2B, TRAF1, TRAF2, TRAF4, TRAF7, TRAIP, TRANK1, TRAP1, TRAPPC12-AS1,TRAPPC5, TRAPPC6A, TRBC2, TRBV26OR9-2, TRDN, TREH, TRH, TRHDE-AS1, TRHR,TRIL, TRIM16, TRIM17, TRIM22, TRIM24, TRIM28, TRIM3, TRIM36, TRIM41,TRIM45, TRIM46, TRIM5, TRIM50, TRIM55, TRIM58, TRIM6, TRIM62, TRIM67,TRIM71, TRIM73, TRIM74, TRIOBP, TRIP13, TRIP6, TRMT2A, TRMT2B-AS1, TRO,TROAP, TRPA1, TRPC4, TRPC4AP, TRPC5, TRPC7, TRPC7-AS1, TRPM4, TRPM5,TRPT1, TRPV1, TRPV2, TRPV4, TRPV5, TRRAP, TRUB2, TSC2, TSC22D4, TSEN54,TSGA10IP, TSHR, TSKS, TSKU, TSNARE1, TSNAXIP1, TSPAN10, TSPAN11,TSPAN14, TSPAN15, TSPAN18, TSPAN32, TSPAN33, TSPAN4, TSPAN6, TSPY26P,TSSC1, TSSC1-IT1, TSSC4, TSSK3, TSSK4, TST, TTBK1, TTC12, TTC16, TTC24,TTC29, TTC31, TTC34, TTC36, TTC38, TTC39DP, TTC40, TTC6, TTC9B, TTK,TTLL1, TTLL10, TTLL10-AS1, TTLL12, TTLL3, TTLL6, TTLL9, TTN-AS1, TTR,TTYH1, TTYH3, TUBA3D, TUBA3FP, TUBA4B, TUBB2B, TUBB3, TUBB4A, TUBB8,TUBBP2, TUBBP5, TUBGCP2, TUBGCP6, TUFMP1, TUSC3, TUSC5, TXNDC12, TXNRD2,TYRO3, TYSND1, U1, U2, U2AF1L4, U3, U4, U4atac, U52111.14, U52112.12,U6, U6atac, U7, U73166.2, U73167.7, U8, U82695.9, UACA, UBA52P5,UBASH3B, UBBP1, UBE2C, UBE2E1-AS1, UBE2L6, UBE2NL, UBE2O, UBE2Q1,UBE2R2, UBE2S, UBE2SP1, UBE2SP2, UBE3AP2, UBQLN4P1, UBQLNL, UBXN7-AS1,UCKL1, UCN2, UCP2, UCRC, UFC1, UGT2B11, UGT2B4, UGT2B7, UGT3A1, UGT3A2,UHRF1, UHRF2P1, ULBP3, ULK1, ULK2, UNC119, UNC13B, UNC13C, UNC45B,UNC5A, UNC5B, UNC5C, UNC93B1, UNC93B6, UNCX, UOX, UPB1, UPF3A, UPK1A,UPK1A-AS1, UPK1B, UPK3A, UPK3B, UPP2-IT1, URM1, UROC1, USF1, USF2,USH1C, USH2A, USHBP1, USP11, USP12-AS2, USP18, USP19, USP20, USP22,USP24, USP27X, USP30-AS1, USP32P3, USP47, USP49, USP5, USP9YP10,USP9YP5, UST, VAC14, VANGL1, VANGL2, VASH1, VASN, VAT1, VAV2, VCAN,VCAN-AS1, VDAC1P4, VEGFB, VEGFC, VENTX, VEPH1, VGLL1, VGLL2, VGLL3,VIL1, VIM, VIPR1, VIPR1-AS1, VIPR2, VIT, VMAC, VN1R48P, VN2R17P, VNN2,VNN3, VPS11, VPS13A-AS1, VPS28, VPS37D, VPS51, VPS53, VPS8, VRK1, VRTN,VSIG1, VSIG10L, VSIG2, VSTM2, VSTM2A, VSTM2B, VSTM2L, VSTM4, VSTM5,VTCN1, VTN, VWA1, VWA2, VWA5B1, VWA5B2, VWCE, WAS, WASF1, WASH2P,WASH7P, WBP1, WBP1L, WBSCR16, WBSCR17, WBSCR28, WDR13, WDR18, WDR24,WDR27, WDR34, WDR48, WDR54, WDR59, WDR6, WDR60, WDR62, WDR64, WDR72,WDR81, WDR86, WDR86-AS1, WDR87, WDR90, WDTC1, WEE1, WFDC1, WFDC2, WHSC1,WI2-81516E3.1, WI2-89031B12.1, WIPF3, WISP2, WIZ, WNK2, WNK4, WNT1,WNT11, WNT5A, WNT5B, WNT6, WNT8A, WNT8B, WNT9B, WSB1, WTIP, WWC2, WWTR1,XAGE2B, XCL1, XIRP2, XKR4, XKR5, XKR7, XKR8, XKRX, XPNPEP1, XRCC1,XRCC2, XRCC3, XXbac-B135H6.15, XXbac- B33L19.4, XXbac-B444P24.8,XXbac-B461K10.4, XXbac-B562F10.11, XXbac- BPG181M17.6, XXbac-BPG55C20.3,XX-C283C717.1, XXyac-YM21GA2.4, XXYLT1, XYLT1, Y_RNA, YAF2, YAP1,YAP1P1, YBX1P4, YBX1P6, YBX2, YIPF7, YPEL1, YPEL3, YPEL4, yR211F11.2,YWHAZP4, YWHAZP6, Z83844.1, Z93241.1, Z95704.5, Z98256.1, ZACN, ZAP70,ZBED1, ZBED4, ZBTB12B, ZBTB16, ZBTB32, ZBTB37, ZBTB45, ZBTB46, ZBTB48,ZBTB7C, ZBTB8B, ZC3H12D, ZCCHC11, ZCCHC12, ZCCHC24, ZCCHC3, ZDHHC1,ZDHHC11, ZDHHC12, ZDHHC16, ZDHHC22, ZDHHC8, ZDHHC8P, ZDHHC8P1, ZEB2P1,ZER1, ZFAND2B, ZFAT, ZFHX2, ZFHX4, ZFP42, ZFP90, ZFP91-CNTF, ZFP92,ZFPM1, ZFPM2, ZFR2, ZFX, ZFX-AS1, ZFYVE1, ZFYVE19, ZFYVE21, ZG16B, ZIC1,ZIC2, ZIC3, ZIC5, ZMAT4, ZMIZ2, ZMYM2-IT1, ZMYM3, ZMYM4-AS1, ZMYND15,ZMYNDI9, ZNF133, ZNF157, ZNF192P1, ZNF192P2, ZNF205, ZNF217, ZNF219,ZNF26, ZNF264, ZNF276, ZNF281, ZNF282, ZNF296, ZNF300, ZNF316, ZNF319,ZNF335, ZNF346, ZNF358, ZNF362, ZNF385A, ZNF385B, ZNF385C, ZNF408,ZNF414, ZNF423, ZNF428, ZNF431, ZNF444, ZNF445, ZNF446, ZNF467, ZNF469,ZNF474, ZNF48, ZNF488, ZNF497, ZNF500, ZNF512B, ZNF517, ZNF518A, ZNF521,ZNF532, ZNF534, ZNF536, ZNF541, ZNF557, ZNF560, ZNF578, ZNF579, ZNF581,ZNF608, ZNF618, ZNF628, ZNF629, ZNF646, ZNF652P1, ZNF653, ZNF66P,ZNF677, ZNF678, ZNF687, ZNF688, ZNF689, ZNF69, ZNF692, ZNF695, ZNF696,ZNF703, ZNF704, ZNF705E, ZNF707, ZNF71, ZNF710, ZNF711, ZNF713, ZNF714,ZNF724P, ZNF726, ZNF730, ZNF738, ZNF74, ZNF740, ZNF764, ZNF768, ZNF771,ZNF775, ZNF777, ZNF784, ZNF786, ZNF787, ZNF788, ZNF804A, ZNF807, ZNF812,ZNF815P, ZNF821, ZNF837, ZNF84, ZNF843, ZNF847P, ZNF85, ZNF853, ZNF865,ZNF883, ZNF90, ZNRF1, ZNRF4, ZP2, ZSCAN1, ZSCAN2, ZSCAN5B, ZSCAN5C,ZSWIM4, ZSWIM7, ZWILCH, ZWINT

It is to be understood that the levels of expression of one or more ofthe genes listed in Table 4 are depicted in FIG. 5C as a fold change inexpression of in vitro-differentiated insulin-positive β-like cellscompared to mature β-cells.

It should also be appreciated that any gene listed in Table 4 can beused as a marker for detecting immature β-cells or invitro-differentiated insulin-positive β-like cells by measuring thelevel of expression of the gene in a cell, culture, cell line, tissue,or population of cells (e.g., suspected of being β-cells), wherein ifthe level of expression of the gene in the cell, culture, cell line,tissue, or population of cells is elevated (for example, as depicted inFIG. 5C), the cell, culture, cell line, tissue, or population of cellscomprises immature β-cells or in vitro-differentiated insulin-positiveβ-like cells.

Those skilled in the art will also appreciate that any two or more ofthe genes listed in Table 4 can be used in combinations of up to N genes(where N is a positive integer greater than or equal to 2) as markersfor detecting immature β-cells or in vitro-differentiatedinsulin-positive β-like cells by measuring the levels of expression ofthe combination of genes in a cell, culture, cell line, tissue, orpopulation of cells (e.g., suspected of being β-cells), wherein if thelevels of expression of the combination of genes in the cell, culture,cell line, tissue, or population of cells is elevated (for example, asdepicted in FIG. 5C), the cell, culture, cell line, tissue, orpopulation of cells comprises immature β-cells or invitro-differentiated insulin-positive β-like cells.

In some aspects, the present invention provides a method of identifyingthe functional maturity of β-cells. An exemplary method of identifyingthe functional maturity of β-cells comprises (a) obtaining a putativeβ-cell or a population of putative β-cells; and (b) detecting anexpression level in the β-cell or the population of β-cells of one ormore genes listed in Table 1, Table 2, Table 3 or Table 4, wherein: (i)an elevated level of expression of one or more genes listed in Table 1or Table 2 in the β-cell or the population of β-cells indicates that theβ-cell or the population of β-cells are functionally mature β-cells; and(ii) an elevated level of expression of one or more genes listed inTable 3 or Table 4 in the β-cell or the population of β-cells indicatesthat the β-cell or the population of β-cells are functionally immatureβ-cells.

In some aspects, the present invention provides a method of identifyingmature β-cells. An exemplary method of identifying mature β-cellscomprises (a) obtaining a putative β-cell or a population of putativeβ-cells; and (b) detecting an expression level in the β-cell or thepopulation of β-cells of one or more genes listed in Table 1 or Table 2,wherein: (i) an elevated level of expression of one or more genes listedin Table 1 or Table 2 in the β-cell or the population of β-cellsindicates that the β-cell or the population of β-cells are matureβ-cells.

In some embodiments of this and other aspects of the invention, thepresence of elevated levels expression comprises at least a 2 foldincrease, a 3 fold increase, a 4 fold increase, a 5 fold increase, orN-fold increase (where N is a positive integer) in the levels ofexpression of the one or more genes listed in Table 1 or Table 2 in theβ-cell or the population of β-cells compared to the levels of expressionof the same one or more genes in immature β-cells.

In some embodiments of this and other aspects of the invention, thepresence of elevated levels expression comprises at least a 2 foldincrease, a 3 fold increase, a 4 fold increase, a 5 fold increase, orN-fold increase (where N is a positive integer) in the levels ofexpression of the one or more genes listed in Table 3 or Table 4 in theβ-cell or the population of β-cells compared to the levels of expressionof the same one or more genes in mature β-cells.

In some aspects, the present invention provides a method of identifyingfetal β-cells. An exemplary method of identifying fetal β-cellscomprises (a) obtaining a putative β-cell or a population of putativeβ-cells; and (b) detecting an expression level in the β-cell or thepopulation of β-cells of one or more genes listed in Table 3, wherein:(i) an elevated level of expression of one or more genes listed in Table3 in the β-cell or the population of β-cells indicates that the β-cellor the population of β-cells are fetal β-cells.

In some embodiments of this and other aspects of the invention, thepresence of elevated levels expression comprises at least a 2 foldincrease, a 3 fold increase, a 4 fold increase, a 5 fold increase, orN-fold increase (where N is a positive integer) in the levels ofexpression of the one or more genes listed in Table 3 in the β-cell orthe population of β-cells compared to the levels of expression of thesame one or more genes in mature β-cells.

In some aspects, the present invention provides a method of identifyingin vitro-differentiated insulin-positive β-like cells. An exemplarymethod of identifying in vitro-differentiated insulin-positive β-likecells, comprises: (a) obtaining a putative β-cell or the population ofputative β-cells; and (b) detecting an expression level in the β-cell orthe population of β-cells of one or more genes listed in Table 4,wherein: (i) an elevated level of expression of one or more genes listedin Table 4 in the β-cell or the population of β-cells indicates that theβ-cell or the population of β-cells are in vitro-differentiatedinsulin-positive β-like cells.

In some embodiments of this and other aspects of the invention, thepresence of elevated levels expression comprises at least a 2 foldincrease, a 3 fold increase, a 4 fold increase, a 5 fold increase, orN-fold increase (where N is a positive integer) in the levels ofexpression of the one or more genes listed in Table 4 in the β-cell orthe population of β-cells compared to the levels of expression of thesame one or more genes in mature β-cells.

In some embodiments of this and other aspects of the invention, theelevated levels expression of the one or more genes listed in Table 3and Table 4 are depicted in FIG. 5C. Those skilled in the art willappreciate how to interpret the negative relative expression levelsdepicted in FIG. 5C as positive levels of elevated expression.

In some embodiments of this and other aspects of the invention, theelevated levels expression of the one or more genes listed in Tables 2and 4 are depicted in FIG. 5C. Those skilled in the art will appreciatehow to interpret the negative relative expression levels depicted inFIG. 5C as positive levels of elevated expression.

In some aspects, an exemplary method of distinguishing mature andimmature β-cells comprises: (a) obtaining a putative β-cell or apopulation of putative β-cells; (b) measuring expression of a group ofgenes in the β-cell or the population of β-cells to produce anexpression profile of the β-cell or the population of β-cells; (c)comparing the expression profile of the β-cell or the population ofβ-cells to any or all of: (i) a reference mature β-cell expressionprofile selected from the group consisting of a first group of geneshaving higher expression levels in mature β-cells compared to fetalβ-cells, wherein the first group of genes is selected from the groupconsisting of STAT4, NPAS2, STAT3, NPAS2, STAT3, PBX3, NR3C2, DDIT3,SIX4, ETV5, SIX2, TP53, BCL6, MESP1, HOPX, BHLHB3, EPAS1, KCNK3, GPI,CHGB, ALDOA, MAFA, SYT7, IAPP, WNT4, PDK3, KCNK1, SLC2A2, ESR1, G6PC2,and a second group of genes having higher expression levels in matureβ-cells compared to insulin-positive β-like cells, wherein the secondgroup of genes is selected from the group consisting of XBP1, NFIA,PURA, PDX1, NR3C2, MNX1, GLIS3, EPAS1, HSF4, TSHZ3, MAFA, NKX6-1, HOPX,RORC, NFIX, PEG3, CEBPD, KLF9, STX1A, KCNMA1, PDX1, CHGB, MNX1, PCSK2,NKX6.1, GLIS3, KCNK12, KCNK3, GCGR, KCNK1, SLC30A8, PCSK1, MAFA, ESR1,SLC2A2, IAPP, G6PC2, STXBP1, KCNH2, KCNMB2, UCN3, and WNT4; and (ii) areference immature fetal β-cell expression profile selected from thegroup consisting of a third group of genes having higher expressionlevels in fetal β-cells compared to mature β-cells, wherein said thirdgroup of genes is selected from the group consisting of LZTS1, EVI1,MYCN, FOS, EGR1, RCOR2, TCF3, ASCL2, NOTCH1, LMO4, PAX4, NFIB, ISX,SOX11, LHX4, ZNF423, SOX8, RFX1, PROX1, HHEX, CSRNP3, LZTR1, SOX4,NKX6.2, COL1A1, PAX4, KCNH6, RIMS3, PROX1, SOX4, ACSS1, GHRL, NOTCH1,KCNN3, GCK, PYY, HCN3, KCNJ4, and a fourth group of genes having higherexpression levels in insulin-positive β-like cells compared to matureβ-cells, wherein said fourth group of genes is selected from the groupconsisting of FOXA1, HHEX, NR2F1, FEV, IRX2, SOX11, PAX4, ONECUT2, LMO4,AEBP1, HES6, TGIF2, LZTS1, TCF3, GATA4, ARX, EGR1, RCOR2, CEBPA, ELF4,HNF4G, PBX2, ISX, ZNF217, NTS, GAST, RIMS3, CACNA1E, PYY, SCT, FOXA1,GATA4, KCNH6, ARX, DLL3, NOTCH1, IRX2, DPP4, PAX4, ACOX2, KCNB1, PROX1,GHRL, SLC2A1, ONECUT2, and SLC2A3; and (d) distinguishing mature andimmature β-cells, wherein the β-cell or the population of β-cells are:(i) mature β-cells if the expression profile of the β-cell or thepopulation of β-cells exhibits a pattern of expression similar to eitherreference mature β-cell expression profile; or (ii) immature β-cells ifthe expression profile of the β-cell or the population of β-cellsexhibits a pattern of expression similar to either reference immatureβ-cell expression profile expression profile.

Signaling Pathways Enriched in Mature and Immature β-Cells

The present invention contemplates distinguishing mature and immatureβ-cells by assessing enrichment of one or more signaling pathwaysenriched in mature and/or immature β-cells in a β-cell or population ofβ-cells.

Generally, detecting enrichment of a signaling pathway enriched inmature β-cells compared to fetal β-cells or in vitro-differentiatedinsulin-positive β-like cells in a β-cell or population of β-cells isindicative that the β-cell or population of β-cells is functionallymature, whereas detecting the absence of enrichment of the samesignaling pathway in the β-cell or population of β-cells may beindicative that the β-cell or population of β-cells is functionallyimmature. Conversely, detecting enrichment of a signaling pathwayenriched in fetal β-cells or in vitro-differentiated insulin-positiveβ-like cells compared to mature β-cells in a β-cell or population ofβ-cells is indicative that the β-cell or population of β-cells isfunctionally immature, whereas detecting the absence of enrichment ofthe same signaling pathway in the β-cell or population of β-cells may beindicative that the β-cell or population of β-cells is functionallymature.

The present invention contemplates assessing enrichment of a signalingpathway according to any technique available to the skilled artisan. Insome embodiments of this and other aspects of the invention, detectingthe presence or absence of enrichment of signaling pathways comprisesconducting a Gene Set Enrichment Analysis (GSEA).

In some aspects, one or more markers of β-cell functional maturityinclude signaling pathways which are enriched in mature β-cells comparedto fetal β-cells or in vitro-differentiated insulin-positive β-likecells.

In some aspects, one or more markers of β-cell functional immaturityinclude signaling pathways which are enriched in fetal β-cells or invitro-differentiated insulin-positive β-like cells compared to matureβ-cells.

In some aspects, an exemplary method of distinguishing mature andimmature β-cells comprises: (a) obtaining a putative β-cell or apopulation of putative β-cells; (b) assessing enrichment of a signalingpathway to produce a signaling pathway enrichment plot of the β-cell orthe population of β-cells, wherein the signaling pathway is selectedfrom the group consisting of an unfolded protein response signalingpathway, an insulin synthesis and secretion signaling pathway, and ametal ion SLC transporters signaling pathway; and (c) distinguishingmature and immature β-cells, wherein the β-cell or the population ofβ-cells are: (i) mature β-cells if the signaling pathway enrichment plotof the β-cell or the population of β-cells indicates that at least oneof the unfolded protein response signaling pathway, the insulinsynthesis and secretion signaling pathway, and the metal ion SLCtransporters signaling pathway are enriched in the β-cell or thepopulation of β-cells; or (ii) immature β-cells if the signaling pathwayenrichment plot of the β-cell or the population of β-cells indicatesthat none of the unfolded protein response signaling pathway, theinsulin synthesis and secretion signaling pathway, and the metal ion SLCtransporters signaling pathway are enriched in the β-cell or thepopulation of β-cells.

Biological Processes Enriched in Mature and Immature β-Cells

The present invention contemplates distinguishing mature and immatureβ-cells by assessing enrichment of one or more biological processesenriched in mature and/or immature β-cells in a β-cell or population ofβ-cells.

Generally, detecting enrichment of a biological process enriched inmature β-cells compared to fetal β-cells or in vitro-differentiatedinsulin-positive β-like cells in a β-cell or population of β-cells isindicative that the β-cell or population of β-cells is functionallymature, whereas detecting the absence of enrichment of the samebiological process in the β-cell or population of β-cells may beindicative that the β-cell or population of β-cells is functionallyimmature. Conversely, detecting enrichment of a biological processenriched in fetal β-cells or in vitro-differentiated insulin-positiveβ-like cells compared to mature β-cells in a β-cell or population ofβ-cells is indicative that the β-cell or population of β-cells isfunctionally immature, whereas detecting the absence of enrichment ofthe same biological process in the β-cell or population of β-cells maybe indicative that the β-cell or population of β-cells is functionallymature.

The present invention contemplates assessing enrichment of biologicalprocesses according to any technique available to the skilled artisan.In some embodiments of this and other aspects of the invention,assessing enrichment of biological processes comprises conducting a GeneOntology (GO). In some embodiments, the Gene Ontology comprises DAVID'sGene Ontology.

In some aspects, one or more markers of β-cell functional maturityinclude biological processes which are enriched in mature β-cellscompared to fetal β-cells or in vitro-differentiated insulin-positiveβ-like cells.

In some aspects, one or more markers of β-cell functional immaturityinclude biological processes which are enriched in fetal β-cells or invitro-differentiated insulin-positive β-like cells compared to matureβ-cells.

In some aspects, an exemplary method of distinguishing mature andimmature β-cells, comprises: (a) obtaining a putative β-cell or apopulation of putative β-cells; (b) assessing enrichment of a biologicalprocess to determine if the biological process is enriched in the β-cellor the population of β-cells, wherein the biological process is selectedfrom the group consisting of: (i) generation of precursor metabolitesand energy, (ii) oxidation reduction, (iii) vesicle-mediated transport,(iv) electron transport chain, (v) monosaccharide metabolic process,(vi) cell morphogenesis, (vii) cellular component morphogenesis, (viii)cell projection organization, (ix) Wnt receptor signaling pathway, (x)cell projection morphogenesis, (xi) cytoskeleton organization, (xii)sterol biosynthetic process, (xiii) cholesterol biosynthetic process,(xiv) actin filament-based process, (xv) actin cytoskeletonorganization, (xvi) sterol metabolic process, and (xvii) neuronprojection development; (c) distinguishing mature and immature β-cells,wherein the β-cell or the population of β-cells are: (i) mature β-cellsif at least one of the biological processes selected from the groupconsisting of (i), (ii), (iii), (iv), and (v) is enriched in the β-cellor the population of β-cells; or (ii) immature β-cells if at least oneof the biological processes selected from the group consisting of (vi),(vii), (viii), (ix), (x), (xi), (xii), (xiii), (xiv), (xv), (xvi), and(xvii) is enriched in the β-cell or the population of β-cells.

Methods of Identifying Agents that Modulate β-Cell Maturity

The markers of the present invention can be measured in β-cells orpopulations of β-cells to assay for agents that modulate β-cell maturity(e.g., agents that induce β-cells to mature into functionally matureβ-cells or agents that induce mature β-cells to become functionallyimmature β-cells). Identification of agents (or factors) that inducefunctional β-cell maturation can be used for the in vitro production ofa virtually unlimited supply of functionally mature β-cells foradministration to a human or animal in need of such functionally matureβ-cells (e.g., an individual suffering from a disorder associated withimmature β-cells, e.g., diabetes). Identification of agents (or factors)that induce mature β-cells to dedifferentiate into functionally immatureβ-cells can be used to understand mechanisms underlying disordersassociated with immature β-cells, as well as to identify conditions inculture which might need to be inhibited to produce functionally matureβ-cells in vitro.

Accordingly, in some aspects, the present invention provides methods ofidentifying a candidate agent that modulates the functional maturity ofβ-cells.

An exemplary method of identifying a candidate agent that modulates thefunctional maturity of β-cells, comprises: (a) contacting a β-cell or apopulation of β-cells with a test agent; (b) monitoring expression of agroup of genes in the β-cell or the population of β-cells, in thepresence of the test agent, to produce an expression profile of theβ-cell or the population of β-cells; (c) comparing the expressionprofile of the β-cell or the population of β-cells to: (i) a referencemature β-cell expression profile selected from the group consisting of afirst group of genes having higher expression levels in mature β-cellscompared to fetal β-cells, wherein the first group of genes is selectedfrom the group consisting of KCNK3, GPI, CHGB, ALDOA, MAFA, SYT7, IAPP,WNT4, PDK3, KCNK1, SLC2A2, ESR1, G6PC2, and a second group of geneshaving higher expression levels in mature β-cells compared toinsulin-positive β-like cells, wherein the second group of genes isselected from the group consisting of STX1A, KCNMA1, PDX1, CHGB, MNX1,PCSK2, NKX6.1, GLIS3, KCNK12, KCNK3, GCGR, KCNK1, SLC30A8, PCSK1, MAFA,ESR1, SLC2A2, IAPP, G6PC2, STXBP1, KCNH2, KCNMB2, UCN3, and WNT4; (ii) areference immature β-cell expression profile selected from the groupconsisting of a third group of genes having higher expression levels infetal β-cells compared to mature β-cells, wherein said third group ofgenes is selected from the group consisting of NKX6.2, COL1A1, PAX4,KCNH6, RIMS3, PROX1, SOX4, ACSS1, GHRL, NOTCH1, KCNN3, GCK, PYY, HCN3,and KCNJ4, and a fourth group of genes having higher expression levelsin insulin-positive β-like cells compared to mature β-cells, whereinsaid fourth group of genes is selected from the group consisting of NTS,GAST, RIMS3, CACNA1E, PYY, SCT, FOXA1, GATA4, KCNH6, ARX, DLL3, NOTCH1,IRX2, DPP4, PAX4, ACOX2, KCNB1, PROX1, GHRL, SLC2A1, ONECUT2, andSLC2A3; and (d) identifying the test agent as a candidate agent thatmodulates the functional maturity of β-cells, wherein: (i) the testagent is a candidate agent that induces β-cells to become functionallymature if the β-cell or the population of β-cells exhibits a pattern ofexpression similar to the either reference mature β-cell expressionprofile in the presence of the test agent; (ii) the test agent is acandidate agent that induces β-cells to become functionally immature ifthe β-cell or the population of β-cells exhibits a pattern of expressionsimilar to either reference immature β-cell expression profile.

Another exemplary method of identifying a candidate agent that modulatesthe functional maturity of β-cells, comprises: (a) contacting a β-cellor a population of β-cells with a test agent; (b) assessing enrichmentof a signaling pathway in the presence of the test agent to produce asignaling pathway enrichment plot of the β-cell or the population ofβ-cells, wherein the signaling pathway is selected from the groupconsisting of an unfolded protein response signaling pathway, an insulinsynthesis and secretion signaling pathway, and a metal ion SLCtransporters signaling pathway; (c) identifying the test agent as acandidate agent that modulates the functional maturity of β-cells,wherein: (i) the test agent is a candidate agent that induces β-cells tobecome functionally mature if the signaling pathway enrichment plot ofthe β-cell or the population of β-cells indicates that at least one ofthe unfolded protein response signaling pathway, the insulin synthesisand secretion signaling pathway, and the metal ion SLC transporterssignaling pathway are enriched in the β-cell or the population ofβ-cells; or (ii) the test agent is a candidate agent that inducesβ-cells to become functionally immature if the signaling pathwayenrichment plot of the β-cell or the population of β-cells indicatesthat none of the unfolded protein response signaling pathway, theinsulin synthesis and secretion signaling pathway, and the metal ion SLCtransporters signaling pathway are enriched in the β-cell or thepopulation of β-cells.

Still another exemplary method of identifying a candidate agent thatmodulates the functional maturity of β-cells, comprises: (a) contactinga β-cell or a population of β-cells with a test agent; (b) assessingenrichment of a biological process in the presence of the test agent todetermine if the biological process is enriched in the β-cell or thepopulation of β-cells, wherein the biological process is selected fromthe group consisting of (i) generation of precursor metabolites andenergy, (ii) oxidation reduction, (iii) vesicle-mediated transport, (iv)electron transport chain, (v) monosaccharide metabolic process, (vi)cell morphogenesis, (vii) cellular component morphogenesis, (viii) cellprojection organization, (ix) Wnt receptor signaling pathway, (x) cellprojection morphogenesis, (xi) cytoskeleton organization, (xii) sterolbiosynthetic process, (xiii) cholesterol biosynthetic process, (xiv)actin filament-based process, (xv) actin cytoskeleton organization,(xvi) sterol metabolic process, and (xvii) neuron projectiondevelopment; and (c) identifying the test agent as a candidate agentthat modulates the functional maturity of β-cells, wherein: (i) the testagent is a candidate agent that induces β-cells to become functionallymature if at least one biological process selected from the groupconsisting of (i), (ii), (iii), (iv), and (v) is enriched in the β-cellor the population of β-cells; or (ii) the test agent is a candidateagent that induces β-cells to become functionally immature if at leastone biological process selected from the group consisting of (vi),(vii), (viii), (ix), (x), (xi), (xii), (xiii), (xiv), (xv), (xvi), and(xvii) is enriched in the β-cell or the population of β-cells.

It should be appreciated that candidate β-cell maturity modulatingagents identified according to the methods of the invention may be usedin methods of treating disorders associated with immature β-cells. Forexample, an agent that induces immature β-cells to become functionallymature β-cells can be used to treat a disorder associated with immatureβ-cells. Accordingly, in some embodiments of this and other aspects ofthe invention, the candidate agent is a candidate agent that modulates adisorder associated with immature β-cells. In some embodiments of thisand other aspects of the invention, the disorder is diabetes. In someembodiments of this and other aspects of the invention, the disorder ispre-diabetes.

Those skilled in the art will appreciate how to perform theidentification methods (e.g., identifying agents for modulating β-cellmaturity, identifying agents that modulate disorders associated withimmature β-cells, etc.) of present invention using routine protocolsavailable to the skilled artisan (e.g., high-throughput screening,combinatorial chemistry, in silico screening, etc.).

It should be appreciated that a wide variety of test agents can be usedin the methods (e.g., a small molecule, polypeptide, peptide, nucleicacid, oligonucleotide, lipid, carbohydrate, or hybrid molecule).

In another aspect, the present invention provides methods of identifyingthe functional maturity of an individual's β-cells.

An exemplary method of identifying the functional maturity of anindividual's β-cells, comprises: (a) obtaining a biological samplecomprising β-cells from the individual; (b) measuring expression of agroup of genes in the biological sample to produce an expression profileof the individual's β-cells; (c) comparing the expression profile of theindividual's β-cells to: (i) a reference mature β-cell expressionprofile selected from the group consisting of a first group of geneshaving higher expression levels in mature β-cells compared to fetalβ-cells, wherein the first group of genes is selected from the groupconsisting of KCNK3, GPI, CHGB, ALDOA, MAFA, SYT7, IAPP, WNT4, PDK3,KCNK1, SLC2A2, ESR1, G6PC2, and a second group of genes having higherexpression levels in mature β-cells compared to insulin-positive β-likecells, wherein the second group of genes is selected from the groupconsisting of STX1A, KCNMA1, PDX1, CHGB, MNX1, PCSK2, NKX6.1, GLIS3,KCNK12, KCNK3, GCGR, KCNK1, SLC30A8, PCSK1, MAFA, ESR1, SLC2A2, IAPP,G6PC2, STXBP1, KCNH2, KCNMB2, UCN3, and WNT4; and (ii) a referenceimmature β-cell expression profile selected from the group consisting ofa third group of genes having higher expression levels in fetal β-cellscompared to mature β-cells, wherein said third group of genes isselected from the group consisting of NKX6.2, COL1A1, PAX4, KCNH6,RIMS3, PROX1, SOX4, ACSS1, GHRL, NOTCH1, KCNN3, GCK, PYY, HCN3, andKCNJ4, and a fourth group of genes having higher expression levels ininsulin-positive β-like cells compared to mature β-cells, wherein saidfourth group of genes is selected from the group consisting of NTS,GAST, RIMS3, CACNA1E, PYY, SCT, FOXA1, GATA4, KCNH6, ARX, DLL3, NOTCH1,IRX2, DPP4, PAX4, ACOX2, KCNB1, PROX1, GHRL, SLC2A1, ONECUT2, andSLC2A3; and (d) identifying the functional maturity of the individual'sβ-cells, wherein: (i) the individual's β-cells are functionally matureif the β-cell in the biological sample exhibit a pattern of expressionsimilar to either reference mature β-cell expression profile; or (ii)the individual's β-cells are functionally immature if the β-cells in thebiological sample exhibit a pattern of expression similar to eitherreference immature β-cell expression profile.

Another exemplary method of identifying the functional maturity of anindividual's β-cells, comprises: (a) obtaining a biological samplecomprising β-cells from the individual; (b) assessing enrichment of asignaling pathway to produce a signaling pathway enrichment plot of theβ-cells in the biological sample, wherein the signaling pathway isselected from the group consisting of an unfolded protein responsesignaling pathway, an insulin synthesis and secretion signaling pathway,and a metal ion SLC transporters signaling pathway; (c) identifying thefunctional maturity of the individual's β-cells, wherein: (i) theindividual's β-cells are functionally mature if the signaling pathwayenrichment plot indicates that at least one of the unfolded proteinresponse signaling pathway, the insulin synthesis and secretionsignaling pathway, and the metal ion SLC transporters signaling pathwayare enriched in the β-cell in the biological sample; or (ii) theindividual's β-cells are functionally immature if the signaling pathwayenrichment plot indicates that none of the unfolded protein responsesignaling pathway, the insulin synthesis and secretion signalingpathway, and the metal ion SLC transporters signaling pathway areenriched in the β-cells in the biological sample.

Still another exemplary method of identifying the functional maturity ofan individual's β-cells, comprises: (a) obtaining a biological samplecomprising β-cells from the individual; (b) assessing enrichment of abiological process in the biological sample, wherein the biologicalprocess is selected from the group consisting of (i) generation ofprecursor metabolites and energy, (ii) oxidation reduction, (iii)vesicle-mediated transport, (iv) electron transport chain, (v)monosaccharide metabolic process, (vi) cell morphogenesis, (vii)cellular component morphogenesis, (viii) cell projection organization,(ix) Wnt receptor signaling pathway, (x) cell projection morphogenesis,(xi) cytoskeleton organization, (xii) sterol biosynthetic process,(xiii) cholesterol biosynthetic process, (xiv) actin filament-basedprocess, (xv) actin cytoskeleton organization, (xvi) sterol metabolicprocess, and (xvii) neuron projection development; and (c) identifyingthe functional maturity of the individual's β-cells, wherein: (i) theindividual's β-cells are functionally mature if at least one biologicalprocess selected from the group consisting of (i), (ii), (iii), (iv),and (v) is enriched in the biological sample; or (ii) the individual'sβ-cells are functionally immature if at least one biological processselected from the group consisting of (vi), (vii), (viii), (ix), (x),(xi), (xii), (xiii), (xiv), (xv), (xvi), and (xvii) is enriched in thebiological sample.

The present invention contemplates obtaining a biological samplecomprising β-cells from the individual according to any techniqueavailable to the skilled artisan. The individual from which thebiological sample is obtained may be a healthy individual, or anindividual suffering from a disorder associated with functionallyimmature β-cells.

In some embodiments of this and other aspects of the invention, if theindividual's β-cells are functionally immature, the individual is inneed of functionally mature β-cells.

In some embodiments of this and other aspects of the invention, theindividual is a human or animal.

In some embodiments of this and other aspects of the invention, thefunctional maturity of the individual's β-cells is identified beforeβ-cells are administered to the individual. In some embodiments of thisand other aspects of the invention, the functional maturity of theindividual's β-cells is identified after β-cells have been administeredto the individual.

In some embodiments of this and other aspects of the invention, thebiological sample comprises pancreatic tissue. In some embodiments ofthis and other aspects of the invention, the biological sample comprisesislets of Langerhans.

The markers of the present invention can be used for selectingfunctionally mature β-cells for administration to a human or animalsubject in need of such functionally mature β-cells, as well asdetermining whether in vitro β-like cells administered to a human oranimal subject are functionally mature in vivo.

In some embodiments of this and other aspects of the invention,administering the in vitro-differentiated β-like cells to the human oranimal subject comprises transplanting the β-like cells to the human oranimal subject (e.g., into a kidney capsule of the human or animalsubject). Other suitable methods of administering the invitro-differentiated β-like cells to the human or animal subject areapparent to the skilled artisan.

In some instances, it may be desirable to conduct a glucose tolerancetest on the human or animal subject to detect levels of human fastingC-peptide in the human or animal subject. It should be appreciated thatif the levels of fasting human C-peptide levels detected are above abackground level after administration of β-like cells to the human oranimal subject, the administered β-like cells are functionally mature invivo. In this way, fasting human C-peptide levels can be used as anadditional marker to confirm that the administered β-like cells havefunctionally matured in vivo (e.g., the functionally mature β-like cellsare glucose-responsive β-cells).

In some embodiments of this and other aspects of the invention, theβ-cell or population of β-cells is obtained from an in vitro source.

In some embodiments of this and other aspects of the invention, the invitro source of β-cells is a culture of differentiating stem cells. Asused herein, “stem cell” refers to a cell that has the ability todifferentiate into a cell of any type. Examples of stem cells that canbe used in the methods of the present invention include embryonic stemcells obtained by culturing a pre-implantation early embryo, embryonicstem cells obtained by culturing an early embryo prepared by somaticcell nuclear transfer, and induced pluripotent stem cells obtained bytransferring appropriate transcription factors to a somatic cell toreprogram the cell. A variety of protocols for obtaining the stem cellsfor use in the methods of the present invention are available to theskilled artisan.

In some embodiments of this and other aspects of the invention, the stemcells are human embryonic stem cells (hESCs). In some embodiments ofthis and other aspects of the invention, the stem cells are inducedpluripotent stem cells (iPSCs). In some embodiments of this and otheraspects of the invention, the induced pluripotent stem cells are derivedfrom reprogramming human somatic cells. The human somatic cells can beobtained from a healthy human or a human suffering from a disorderassociated with immature or abnormal β-cells.

β-cells obtained from a culture of differentiating stem cells arereferred to herein as “in vitro-differentiating β-cells” or “invitro-differentiating β-cells.” As used herein, “in vitro-differentiatedβ-cell” refers to a β-cell or β-like cell obtained by differentiating astem cell in vitro. An “in vitro-differentiating β-cell” refers to acell (or cells) in the process of differentiating into a β-cell orβ-like cell.

Generally, the in vitro-differentiated β-cells obtained in accordancewith the methods of the present invention are derived by differentiatingone or more stem cells into β-cells or β-like cells. The presentinvention contemplates any culturing protocol that is capable ofdifferentiating stem cells into β-cells or β-like cells. FIGS. 1A and 1Billustrate exemplary culturing protocols. Additional examples ofsuitable protocols have been reviewed by Liew (Liew C G. Rev Diabet Stud7(2), 82-92 (2010), incorporated herein by reference in its entirety.)

In some embodiments of this and other aspects of the invention, the invitro source includes a cell bank (e.g., cryopreserved β-cells), a cellline, a cell culture (e.g., in vitro-differentiated β-cells), a cellpopulation, and combinations thereof.

In some embodiments of this and other aspects of the invention, the invitro source is an artificial tissue or organ (e.g., a pancreas,pancreatic islets, etc.).

In some embodiments of this and other aspects of the invention, theβ-cell is obtained from an in vivo source.

In some embodiments of this and other aspects of the invention, the invivo source is an individual that has received an administration ofβ-cells. In such embodiments, an individual can be administeredfunctionally mature β-cells (e.g., via transplantation) and the markersand methods of the present invention can be used to confirm that theadministered β-cells remain mature post-administration. Alternatively,an individual can be administered functionally immature β-cells (e.g.,in vitro-differentiated insulin positive β-like cells) and the markersand methods of the present invention can be used to determine whetherthe functionally immature β-cells have matured in vivo.

In some embodiments of this and other aspects of the invention, the invivo source is an individual suffering from a disorder associated withimmature β-cells (e.g., diabetes or pre-diabetes).

In some embodiments of this and other aspects of the invention, the invivo source is an individual suffering from a β-cell disorder selectedfrom the group consisting of a disorder associated with immatureβ-cells, a disorder associated with destruction of β-cells, a disorderassociated with dysfunctional β-cells, and a disorder associated with aninsufficient number of β-cells.

In some embodiments of this and other aspects of the invention, the invivo source is an individual suspected of being in need of functionallymature β-cells. In such embodiments, the methods of identifying thefunctional maturity of β-cells can be adapted for use in methods ofidentifying individuals in need of functionally mature β-cells. Forexample, a biological sample comprising β-cells can be obtained from theindividual and the β-cells in the biological sample can be assessed fortheir maturity in accordance with the methods of the present invention.

In some embodiments of this and other aspects of the invention, the invivo source is a tissue or organ obtained from a donor individual. Insuch embodiments, the markers or methods of the present invention can beused to determine whether the β-cells in the tissue or organ (e.g.,pancreas, islets of Langerhans, etc.) are functionally mature beforetransplanting the tissue or organ into the recipient individual.

In some embodiments of this and other aspects of the invention, theindividual is a human or animal individual.

In some embodiments of this and other aspects of the invention, thepresent invention contemplates sorting the immature and mature β-cellsidentified. Sorting immature and mature β-cells can be helpful forselecting mature β-cells that might be useful for administration to anindividual in need of mature β-cells.

Suitable methods of sorting cells are apparent to the skilled artisan.In some embodiments of this and other aspects of the invention, sortingthe functionally immature and mature β-cells identified in thepopulation of β-cells is achieved by fluorescence-activated cell sorting(FACS). In some embodiments of this and other aspects of the invention,sorting the functionally immature and mature β-cells identified in thepopulation of β-cells is achieved by intracellular-FACS (IC-FACS).

In some embodiments of this and other aspects of the invention, the FACScomprises staining at least one antibody specific for a putative β-cellsurface marker selected from the group consisting of ABCA3, CD79B,FXYD2, KCNB2, NLGN1, PTPRU, SLC6A9, ABCC8, CD8A, GCGR, KCNF1, NPR2,ROBO1, SORL1, ABCG1, CDH2, GPR120, KCNG3, NRCAM, RTN4, SVOP, ACSL1,CDH22, GPR19, KCNH2, PCDHA1, SEMA5A, TGFBR3, ATP1B2, CHRNA5, GRIA2,KCNMA1, PCDHA3, SERP2, TRPM2, CACNA1H, CYB561, KCNH1, KCNQ2, PIGU,SLC17A6, TRPM5, CADM1, EFNB3, IGSF11, MADD, PLXNA2, SLC43A2, TSPAN13,CASR, FFAR1, IL17RB, NEO1, PRRG2, SLC6A6, and UNC5A.

It should be appreciated that FACS analysis can be performed incombination with the methods for detecting markers of the presentinvention to sort β-cells expressing certain markers and quantify thepercentage and levels of expression of those markers, as well as toanalyze global gene expression patterns.

In some embodiments of this and other aspects of the invention, thepresent invention contemplates quantifying the sorted functionallyimmature and mature β-cells identified in the population of β-cells.

In some embodiments of this and other aspects of the invention, thepresent invention contemplates preserving the sorted functionally matureβ-cells (e.g., cryopreservation of the cells in appropriate reagents).

In some embodiments of this and other aspects of the invention, thepresent invention contemplates conducting a GSIS assay on the β-cell orpopulation of β-cells to determine whether the β-cell or the populationof β-cells exhibits an appropriate GSIS response.

In some embodiments of this and other aspects of the invention, themature β-cell is a human β-cell.

In some embodiments of this and other aspects of the invention, thefetal β-cell is a human β-cell.

In some embodiments of this and other aspects of the invention, theinsulin-positive β-like cell is derived from human cells selected fromthe group consisting of human embryonic stem cells, reprogrammed humansomatic cells, and induced human pluripotent stem cells.

In some aspects, the present invention provides a method of delivering amolecule of interest to a β-cell or a population of β-cells. Anexemplary method of delivering a molecule of interest to a β-cell or apopulation of β-cells, comprises: contacting the β-cell or thepopulation of β-cells with a composition comprising the molecule ofinterest conjugated to an antibody that binds to a putative β-cellsurface marker selected from the group consisting of ABCA3, CD79B,FXYD2, KCNB2, NLGN1, PTPRU, SLC6A9, ABCC8, CD8A, GCGR, KCNF1, NPR2,ROBO1, SORL1, ABCG1, CDH2, GPR120, KCNG3, NRCAM, RTN4, SVOP, ACSL1,CDH22, GPR19, KCNH2, PCDHA1, SEMA5A, TGFBR3, ATP1B2, CHRNA5, GRIA2,KCNMA1, PCDHA3, SERP2, TRPM2, CACNA1H, CYB561, KCNH1, KCNQ2, PIGU,SLC17A6, TRPM5, CADM1, EFNB3, IGSF11, MADD, PLXNA2, SLC43A2, TSPAN13,CASR, FFAR1, IL17RB, NEO1, PRRG2, SLC6A6, and UNC5A.

The present invention contemplates delivering any molecule of interestto a β-cell or a population of β-cells. In some embodiments, themolecule of interest is a compound selected from small organic orinorganic molecules; saccharines; oligosaccharides; polysaccharides;biological macromolecules, e.g., peptides, proteins, and peptide analogsand derivatives; peptidomimetics; nucleic acids and nucleic acid analogsand derivatives (including but not limited to siRNAs, shRNAs, antisenseRNAs, a ribozymes, and apatamers); an extract made from biologicalmaterials such as bacteria, plants, fungi, or animal cells; animaltissues; naturally occurring or synthetic compositions; and anycombinations thereof.

As used herein, the term “antibody” includes complete immunoglobulins,antigen binding fragments of immunoglobulins, as well as antigen bindingproteins that comprise antigen binding domains of immunoglobulins.Antigen binding fragments of immunoglobulins include, for example, Fab,Fab′, F(ab′)₂, scFv and dAbs. Modified antibody formats have beendeveloped which retain binding specificity, but have othercharacteristics that may be desirable, including for example,bispecificity, multivalence (more than two binding sites), and compactsize (e.g., binding domains alone). Single chain antibodies lack some orall of the constant domains of the whole antibodies from which they arederived. Therefore, they can overcome some of the problems associatedwith the use of whole antibodies. For example, single-chain antibodiestend to be free of certain undesired interactions between heavy-chainconstant regions and other biological molecules. Additionally,single-chain antibodies are considerably smaller than whole antibodiesand can have greater permeability than whole antibodies, allowingsingle-chain antibodies to localize and bind to target antigen-bindingsites more efficiently. Furthermore, the relatively small size ofsingle-chain antibodies makes them less likely to provoke an unwantedimmune response in a recipient than whole antibodies.

Multiple single chain antibodies, each single chain having one VH andone VL domain covalently linked by a first peptide linker, can becovalently linked by at least one or more peptide linker to formmultivalent single chain antibodies, which can be monospecific ormultispecific. Each chain of a multivalent single chain antibodyincludes a variable light chain fragment and a variable heavy chainfragment, and is linked by a peptide linker to at least one other chain.The peptide linker is composed of at least fifteen amino acid residues.The maximum number of linker amino acid residues is approximately onehundred. Two single chain antibodies can be combined to form a diabody,also known as a bivalent dimer. Diabodies have two chains and twobinding sites, and can be monospecific or bispecific. Each chain of thediabody includes a VH domain connected to a VL domain. The domains areconnected with linkers that are short enough to prevent pairing betweendomains on the same chain, thus driving the pairing betweencomplementary domains on different chains to recreate the twoantigen-binding sites. Three single chain antibodies can be combined toform triabodies, also known as trivalent trimers. Triabodies areconstructed with the amino acid terminus of a VL or VH domain directlyfused to the carboxyl terminus of a VL or VH domain, i.e., without anylinker sequence. The triabody has three Fv heads with the polypeptidesarranged in a cyclic, head-to-tail fashion. A possible conformation ofthe triabody is planar with the three binding sites located in a planeat an angle of 120 degrees from one another. Triabodies can bemonospecific, bispecific or trispecific. Thus, antibodies useful in themethods described herein include, but are not limited to, naturallyoccurring antibodies, bivalent fragments such as (Fab′)₂, monovalentfragments such as Fab, single chain antibodies, single chain Fv (scFv),single domain antibodies, multivalent single chain antibodies,diabodies, triabodies, and the like that bind specifically with anantigen. While both polyclonal and monoclonal antibodies can be used inthe methods described herein, it is preferred that a monoclonal antibodyis used where conditions require increased specificity for a particularprotein. Antibodies can be raised against a putative β-cell surfacemarker by methods known to those skilled in the art. Such methods aredescribed in detail, for example, in Harlow et al., 1988 in: Antibodies,A Laboratory Manual, Cold Spring Harbor, N.Y. Those skilled in the artwill appreciate how to conjugate such antibodies to other molecules ofinterest according to routine methods.

In some embodiments, the contacting occurs in vitro. In someembodiments, the contacting occurs ex vivo. In some embodiments, thecontacting occurs in vivo. In some embodiments, a molecule of interestcan be delivered to a β-cell or a population of β-cells in vivo byadministering the composition to an individual in need of the moleculeof interest.

In some embodiments, the molecule of interest is a therapeutic agentthat has a beneficial effect on β-cells. Examples of such therapeuticagents include, but are not limited to, Metformin or other Biguanides,DPP4 inhibitors, Sulfonylureas or Metiglitinides, SGLT2 inhibitors,Glucokinase activators, Thiazolidinediones, PPARdelta agonists,non-activating PPARgamma modulators, Glp-1 analogs, GIP analogs,Glp-1-receptor agonists, combined Glp-1/GIP receptor agonists, FGF21,agonistic FGFR monoclonal antibodies, Oxyntomodulin analogs, IAPPanalogs, Leptin or Leptin analogs, Adiponectin or Adiponectin analogs,Insulin or Insulin analogs, proton pump inhibitors or gastrin receptoragonists, Reg family proteins/Reg family protein derived peptides oralpha-glucosidase inhibitors.

In some embodiments, the therapeutic agent is capable of modulating aβ-cell associated disorder. In some embodiments, the β-cell associateddisorder is a disorder associated with aberrant insulin production orresponsiveness or aberrant blood glucose levels. Disorders include, butare not limited to, diabetes (e.g., Type I or Type II), gestationaldiabetes, prediabetes, obesity, hyperglycemia, glucose intolerance,insulin resistance, hyperinsulinemia, metabolic syndrome, or syndrome X.The term “diabetes” refers to a disease of a mammalian subject, andincludes Type 1 NIDDM-transient, Type 1 IDDM, Type 2 IDDM-transient,Type 2 NIDDM, or in another embodiment, MODY.

In some aspects, the present invention provides a method of identifyinga candidate agent that modulates differentiation of β-cells. Anexemplary method of identifying a candidate agent that modulatesdifferentiation of β-cells, comprises: (a) contacting a cell, populationof cells, cell line or cell culture with a test agent; and monitoringthe cell, population of cells, cell line, or cell culture for expressionof one or more β-cell specific transcription factors in the presence ofthe test agent, wherein the β-cell specific transcription factors areselected from the group consisting of ASCL2, NR0B1, SIX4, CHD7, TOX,OLIG1, TSHZ3, DACH1, TSNAX, DACH2, MYT1L, PEG3, ZNF10, NDN, ZNF395,ETV5, ZNF540, HOPX, RXRG and ZNF672; and (b) identifying the test agentas a candidate agent that modulates differentiation of β-cells if thecell, population of cells, cell line, or cell culture expresses one ormore of the β-cell specific transcription factors in the presence of thetest agent.

In some aspects, the present invention provides a composition fordifferentiating a precursor cell to a pancreatic β-cell, comprising oneor more β-cell specific transcription factors selected from the groupconsisting of ASCL2, NR0B1, SIX4, CHD7, TOX, OLIG1, TSHZ3, DACH1, TSNAX,DACH2, MYT1L, PEG3, ZNF10, NDN, ZNF395, ETV5, ZNF540, HOPX, RXRG andZNF672.

In some aspects, the present invention provides a method fordifferentiating a precursor cell to a pancreatic β-cell. An exemplarymethod for differentiating a precursor cell to a pancreatic β-cellcomprises causing the precursor cell to upregulate expression of one ormore β-cell specific transcription factors selected from the groupconsisting of ASCL2, NR0B1, SIX4, CHD7, TOX, OLIG1, TSHZ3, DACH1, TSNAX,DACH2, MYT1L, PEG3, ZNF10, NDN, ZNF395, ETV5, ZNF540, HOPX, RXRG andZNF672. The precursor cell can be any cell that is capable ofdifferentiating into a pancreatic β-cell (e.g., iPSCs, hESCs, pancreaticprogenitor cells, etc.). The present invention contemplates causing theprecursor cell to upregulate expression of the one or more β-cellspecific transcription factors. In some embodiments, the precursor cellcan be transfected with a vector comprising a nucleic acid encoding theone or more β-cell specific transcription factors. In some embodiments,causing the precursor cell to upregulate expression of the one or moreβ-cell specific transcription factors comprises contacting the precursorcells with a small molecule that causes the cell to upregulateexpression of the one or more β-cell specific transcription factors. Insome embodiments, causing the cell to upregulate expression of the oneor more β-cell specific transcription factors comprises contacting theprecursor cell with an exogenous β-cell specific transcription factors.In some embodiments, causing the cell to upregulate expression of theone or more β-cell specific transcription factors comprises deliveringan mRNA encoding the one or more β-cell specific transcription factors.In some embodiments, causing the cell to upregulate expression of theone or more β-cell specific transcription factors comprising contactingthe precursor cell with an agent that modulates a signaling pathway thatcauses the one or more β-cell specific transcription factors to beexpressed in the cell. Other suitable methods will be apparent to theskilled artisan.

The invention further provides packaged products and kits, includingpluripotent cells or pancreatic progenitor cells that are capable ofdifferentiating into pancreatic β-cells, cell lines, cell cultures,populations and compositions, including, as well as cells, cultures,populations, and compositions enriched or selected for anydevelopmental, maturation or differentiation stage, packaged intosuitable packaging material. In some embodiments, a packaged product orkit includes pluripotent cells or pancreatic progenitor cells that arecapable of differentiating into pancreatic β-cells, cell lines,cultures, populations or compositions, or a mixed population thereof.

In some aspects, a packaged product or kit includes a label, such as alist of the contents of the package, or instructions for using the kite.g., instructions for culturing, expanding (increasing cell numbers),proliferating, differentiating, maintaining, or delivery, administering,implanting or transplanting in vivo, or screening for a compound oragent that modulates a function or activity of β-cells thereof.

In certain embodiments, a packaged product or kit includes a container,such as a sealed pouch or shipping container, or an article ofmanufacture, for culturing, expanding (increasing cell numbers),proliferating, differentiating, maintaining, or preserving pluripotentcells or pancreatic progenitor cells that are capable of differentiatinginto pancreatic β-cells, such as a tissue culture dish, tube, flask,roller bottle or plate (e.g., a single multi-well plate or dish such asan 8, 16, 32, 64, 96, 384 and 1536 multi-well plate or dish).

In some embodiments, a packaged product or kit includes an article ofmanufacture, for example, an article of manufacture for delivering,administering or transplanting or implanting mature β-cells or invitro-differentiated insulin-positive β-like cells into a subjectlocally, regionally or systemically.

The term “packaging material” refers to a physical structure housing theproduct or components of the kit. The packaging material can maintainthe components sterilely, and can be made of material commonly used forsuch purposes (e.g., paper, corrugated fiber, glass, plastic, foil,ampules, etc.). A label or packaging insert can be included, listingcontents or appropriate written instructions, for example, practicing amethod of the invention.

A packaged product or kit can therefore include instructions forpracticing any of the methods of the invention described herein. Forexample, pluripotent cells or pancreatic progenitor cells that arecapable of differentiating into pancreatic β-cells can be included in atissue culture dish, tube, flask, roller bottle or plate (e.g., a singlemulti-well plate or dish such as an 8, 16, 32, 64, 96, 384 and 1536multi-well plate or dish) together with instructions for culturing,expanding (increasing cell numbers), proliferating, differentiating,maintaining, preserving or screening. In some embodiments, pluripotentcells or pancreatic progenitor cells that are capable of differentiatinginto pancreatic β-cells can be included in a container, pack, ordispenser together with instructions for delivery, administration,implantation or transplantation into a subject in need thereof.

Instructions may be on “printed matter,” e.g., on paper or cardboardwithin the kit, on a label affixed to the package, kit or packagingmaterial, or attached to a tissue culture dish, tube, flask, rollerbottle, plate (e.g., a single multi-well plate or dish such as an 8, 16,32, 64, 96, 384 and 1536 multi-well plate or dish) or vial containing acomponent (e.g., pluripotent cells or pancreatic progenitor cells thatare capable of differentiating into pancreatic β-cells) of the kit.Instructions may comprise voice or video tape and additionally beincluded on a computer readable medium, such as a disk (floppy disketteor hard disk), optical CD such as CD- or DVD-ROM/RAM, magnetic tape,electrical storage media such as RAM and ROM and hybrids of these suchas magnetic/optical storage media.

Invention kits can additionally include cell growth medium, bufferingagent, a preservative, or a cell stabilizing agent. Each component ofthe kit can be enclosed within an individual container or in a mixtureand all of the various containers can be within single or multiplepackages.

Mature β-cells or in vitro-differentiated insulin-positive β-like cells,as well as cell lines, populations, cultures and compositions comprisingthe mature β-cells or in vitro-differentiated insulin-positive β-likecells can be included in or employed in a pharmaceutical formulation. Insome embodiments, a composition comprising a molecule of interestdescribed herein and an antibody that binds to a putative β-cell surfacemarker can be included or employed in a pharmaceutical formulation.

Pharmaceutical formulations include “pharmaceutically acceptable” and“physiologically acceptable” carriers, diluents or excipients. The terms“pharmaceutically acceptable” and “physiologically acceptable” mean thatthe formulation is compatible with pharmaceutical administration. Suchpharmaceutical formulations are useful for treatment of, oradministration or delivery to, or transplanting or implanting into, asubject in vivo or ex vivo.

Pharmaceutical formulations can be made to be compatible with aparticular local, regional or systemic administration or delivery route.Thus, pharmaceutical formulations include carriers, diluents, orexcipients suitable for administration by particular routes. Specificnon-limiting examples of routes of administration for compositions ofthe invention are parenteral, e.g., intravenous, intrarterial,intradermal, intramuscular, subcutaneous, intra-pleural, injection,transdermal (topical), transmucosal, intra-cranial, intra-spinal,intra-ocular, rectal, oral (alimentary), mucosal administration, and anyother formulation suitable for a method or administration protocol.

One skilled in the art readily appreciates that the present invention iswell adapted to carry out the objects and obtain the ends and advantagesmentioned, as well as those inherent therein. The details of thedescription and the examples herein are representative of certainembodiments, are exemplary, and are not intended as limitations on thescope of the invention. Modifications therein and other uses will occurto those skilled in the art. These modifications are encompassed withinthe spirit of the invention. It will be readily apparent to a personskilled in the art that varying substitutions and modifications may bemade to the invention disclosed herein without departing from the scopeand spirit of the invention.

The articles “a” and “an” as used herein in the specification and in theclaims, unless clearly indicated to the contrary, should be understoodto include the plural referents. Claims or descriptions that include“or” between one or more members of a group are considered satisfied ifone, more than one, or all of the group members are present in, employedin, or otherwise relevant to a given product or process unless indicatedto the contrary or otherwise evident from the context. The inventionincludes embodiments in which exactly one member of the group is presentin, employed in, or otherwise relevant to a given product or process.The invention also includes embodiments in which more than one, or allof the group members are present in, employed in, or otherwise relevantto a given product or process. Furthermore, it is to be understood thatthe invention provides all variations, combinations, and permutations inwhich one or more limitations, elements, clauses, descriptive terms,etc., from one or more of the listed claims is introduced into anotherclaim dependent on the same base claim (or, as relevant, any otherclaim) unless otherwise indicated or unless it would be evident to oneof ordinary skill in the art that a contradiction or inconsistency wouldarise. It is contemplated that all embodiments described herein areapplicable to all different aspects of the invention where appropriate.It is also contemplated that any of the embodiments or aspects can befreely combined with one or more other such embodiments or aspectswhenever appropriate. Where elements are presented as lists, e.g., inMarkush group or similar format, it is to be understood that eachsubgroup of the elements is also disclosed, and any element(s) can beremoved from the group. It should be understood that, in general, wherethe invention, or aspects of the invention, is/are referred to ascomprising particular elements, features, etc., certain embodiments ofthe invention or aspects of the invention consist, or consistessentially of, such elements, features, etc. For purposes of simplicitythose embodiments have not in every case been specifically set forth inso many words herein. It should also be understood that any embodimentor aspect of the invention can be explicitly excluded from the claims,regardless of whether the specific exclusion is recited in thespecification. For example, any one or more active agents, additives,ingredients, optional agents, types of organism, disorders, subjects, orcombinations thereof, can be excluded.

Where the claims or description relate to a composition of matter, it isto be understood that methods of making or using the composition ofmatter according to any of the methods disclosed herein, and methods ofusing the composition of matter for any of the purposes disclosed hereinare aspects of the invention, unless otherwise indicated or unless itwould be evident to one of ordinary skill in the art that acontradiction or inconsistency would arise. Where the claims ordescription relate to a method, e.g., it is to be understood thatmethods of making compositions useful for performing the method, andproducts produced according to the method, are aspects of the invention,unless otherwise indicated or unless it would be evident to one ofordinary skill in the art that a contradiction or inconsistency wouldarise.

Where ranges are given herein, the invention includes embodiments inwhich the endpoints are included, embodiments in which both endpointsare excluded, and embodiments in which one endpoint is included and theother is excluded. It should be assumed that both endpoints are includedunless indicated otherwise. Furthermore, it is to be understood thatunless otherwise indicated or otherwise evident from the context andunderstanding of one of ordinary skill in the art, values that areexpressed as ranges can assume any specific value or subrange within thestated ranges in different embodiments of the invention, to the tenth ofthe unit of the lower limit of the range, unless the context clearlydictates otherwise. It is also understood that where a series ofnumerical values is stated herein, the invention includes embodimentsthat relate analogously to any intervening value or range defined by anytwo values in the series, and that the lowest value may be taken as aminimum and the greatest value may be taken as a maximum. Numericalvalues, as used herein, include values expressed as percentages. For anyembodiment of the invention in which a numerical value is prefaced by“about” or “approximately”, the invention includes an embodiment inwhich the exact value is recited. For any embodiment of the invention inwhich a numerical value is not prefaced by “about” or “approximately”,the invention includes an embodiment in which the value is prefaced by“about” or “approximately”. “Approximately” or “about” generallyincludes numbers that fall within a range of 1% or in some embodimentswithin a range of 5% of a number or in some embodiments within a rangeof 10% of a number in either direction (greater than or less than thenumber) unless otherwise stated or otherwise evident from the context(except where such number would impermissibly exceed 100% of a possiblevalue). It should be understood that, unless clearly indicated to thecontrary, in any methods claimed herein that include more than one act,the order of the acts of the method is not necessarily limited to theorder in which the acts of the method are recited, but the inventionincludes embodiments in which the order is so limited. It should also beunderstood that unless otherwise indicated or evident from the context,any product or composition described herein may be considered“isolated”.

EXAMPLES Example 1: The Mature β-Cell Transcriptome and DifferentiallyExpressed Genes, Signaling Pathways, and Biological Processes in Matureand Immature β-Cells Materials and Methods Human Islet Isolation

Fresh human pancreatic islets from non-diabetic donors were obtainedthrough the National Disease Research Interchange (NDRI). The use ofhuman tissue was approved by the Harvard University Committee on the Useof Human Subjects in Research. Clinical information on islet donors islisted in Table 5. Islets were collected with cold ischemia time lessthan 12 hours and shipped overnight in CMRL 1066 media (Invitrogen), 1%human serum albumin, no phenopthalein. The NDRI reported islet purity,as determined through dithizone (diphenylthiocarbazone) staining, andcell viability, as determined by trypan blue exclusion.

Upon arrival, islets were washed with PBS and cultured in CMRL-1066(modified for islet cell culture by Cellgro/Mediatech) with 5% fetalbovine serum (FBS), penicillin (100 U/ml), streptomycin (100 μg/ml), and5.5 mM D-glucose. Islets were gently dispersed by incubation withAccutase at 37° C. for 10 minutes and occasional trituration with aP1000 micropipettor. Undispersed cell aggregates were removed with a 40μm strainer (BD Falcon).

Cells were seeded onto plates coated with Matrigel (BD Biosciences) andcultured for one to seven days before analysis.

TABLE 5 Human islet donor clinical information and islet quality. Donor1 Donor 2 Donor 3 Sex Male Male Female Age (years) 27   19   24   RaceCaucasian Caucasian Caucasian BMI (kg/m2) 30.3 29.2 22.7 Blood type O AB Diabetes no no no Chemo/Rad no no nd* Cause of death head traumatrauma head trauma Islet purity 60-70% 90% 90% Cell viability  >90% 91%90% BMI, body mass index. Chemo/rad, exposure to chemotherapy orradiation therapy. nd*, no data, but medical history indicated nocancer.hESC Culture and Directed Differentiation

Mouse embryonic fibroblast-conditioned media (MEF-CM) was created byincubating media on a confluent mitomycin C-treated layer of MEFs. Themedia consisted of DMEM/F12 supplemented with 20% KnockOut SerumReplacement, 2 mM Glutamax, 1.1 mM β-mercaptoethanol, 1 mM nonessentialamino acids, and 1×penicillin/streptomycin (all from GIBCO). Recombinanthuman basic fibroblast growth factor (bFGF; Invitrogen) was added to themedia at a concentration of 20 ng/ml immediately prior to use. Humanembryonic stem cells (hESCs; H1, NIH designation WA01) were grown inMEF-CM/bFGF and passaged at the ratio of 1:6-1:20 every 4-7 days usingTrypLE Express (a trypsin replacement; Invitrogen) onto tissue culturetreated dishes coated with a 1:30 dilution of growth factor reducedMatrigel (BD Biosciences). At each passage, hESCs were treated with 10μM of the Rho-associated kinase inhibitor Y27632 for 24 hours(Calbiochem). To induce differentiation, hESCs were expanded for two tothree days following a passage until 60-70% confluency. The cells werecultured in ‘basal medium,’ consisting of MCDB 131 (Invitrogen)supplemented with 2% fatty acid-free bovine serum albumin(Proliant/Lampire) and exposed to culture conditions as follows andoutlined in FIG. 1A.

In stage 1 (induction of definitive endoderm), cells were exposed to 100ng/mL activin A (AA; R&D) and 20 ng/mL Wnt3A (R&D) for one day only. Forthree additional days, cells were exposed to 100 ng/mL AA only. In stage2 (induction of primitive foregut), for two days, cells were treatedwith 50 ng/mL FGF7 (Peprotech). In stage 3 (induction of earlypancreatic progenitors), for four days, cells were exposed to 20 ng/mLAA, 50 ng/mL FGF7, 250 nM SANT-1 (Sigma), 2 μM retinoic acid (Sigma),and 100 ng/mL recombinant human noggin (R&D). From stage 3 and forward,the basal media also contained a 1:200 dilution ofinsulin-transferrin-selenium (ITS-X; Invitrogen). In stage 4 (inductionof late pancreatic progenitors), for three days, cells were exposed to250 nM SANT-1, 100 ng/mL noggin, and 100 nM phorbol 12,13-dibutyrate(EMD Biosciences). In stage 5 (induction of endocrine progenitors), forthree days, cells were incubated with 100 ng/mL noggin and 1 μM ALK5inhibitor II (Axxora). In stage 6 (differentiation into endocrinehormone-expressing cells), cells were kept in basal media supplementedwith ITS-X for three to seven days until analysis.

FIG. 1B provides an expanded version of the differentiation protocoldepicted in FIG. 1A. In particular, hPSCs were routinely cultured onhESC-certified matrigel (BD Biosciences) in mTeSR medium (StemcellTechnologies). Cells were passaged at the ratio of 1:6-1:20 every 4-7days using TrypLE Express (Invitrogen). Two different basal medias wereused during differentiation. Basal media 1 (BM-1) contained MCDB-131(Invitrogen) supplemented to 10 mM glucose, 1×GlutaMAX (Gibco, LifeTechnologies), 2.35 g/l NaHCO₃ and 0.1% reagent grade BSA (Proliant).Basal media 2 (BM-2) contained MCDB-131 (Invitrogen) supplemented to 8mM glucose, 1×GlutaMAX (Gibco, Life Technologies), 2.93 g/l NaHCO₃, 2%reagent grade BSA (Proliant), 1:200 ITS-X (Invitrogen) and 44 mg/lVitamin C.

To initiate differentiation the cells were dissociated using TrypLEExpress to single cells and seeded at 150,000 cell/cm2 onto 1:30dilution of growth factor reduced matrigel (BD Biosciences) in DMEM/F12in mTeSR media with 10 uM Y27632 (StemGent). Two days following seedingthe differentiation was started. Day 1 (stage 1.1) cells were exposed toBM-1 supplemented with and 3 uM CHIR-99021 (Stemgent)+100 ng/mlrhActivinA (R&D Systems). Day 2-3 (stage 1.2): BM-1+100 ng/ml rhActivinA(R&D Systems). Day 4-5 (stage 2): BM-1+50 ng/ml FGF7 (Peprotech) (stage2). Day 6-9 (stage 3) BM-2+50 ng/ml FGF7 (Peprotech)+2 μM RA(Sigma)+0.25 μM SANT-1 (Sigma)+20 ng/ml rhActivinA (R&D Systems)+100ng/ml rhNoggin (R&D Systems). Day 10-12 (stage 4) BM-2+100 ng/mlrhNoggin (R&D Systems)+0.25 μM SANT-1 (Sigma)+100 nM PDBu (EMDBiosciences) (stage 4). Day 13-15 (stage 5) BM-2+100 ng/ml rhNoggin (R&DSystems)+1 μM Alk5 inhibitor (Axxora). Day 15 onwards cells were kept inBM-2 media awaiting analysis.

Immunohistochemistry

Dispersed cells were washed with PBS and fixed by immersion in 4%paraformaldehyde (PFA) at room temperature for 20 minutes. Intact isletswere fixed overnight at 4° C. to allow thorough penetration of fixative.Culture plates were blocked by incubation at room temperature for 1 hwith 10% donkey serum (Jackson Immunoresearch) in PBS and 0.1% Triton-X(Sigma). Cells were incubated with primary and then secondary antibodiesin blocking solution each for an hour at room temperature while gentlyrocking (specific antibodies and concentrations listed in Table 6 andTable 7). After each stain, cells were washed by incubation withPBS/0.1% Triton-X for 5 min while rocking at room temperature. Nucleiwere visualized by brief incubation with Hoescht 33342 (Invitrogen;1:5000 in PBS). Images in each fluorescent channel were taken on anOlympus IX51 Microscope.

TABLE 6 Primary antibodies used in study. Dilution Dilution for forManufac- Catalog IHC/ West- Antigen Species turer # FACS erns Insulinguinea Dako A0564  1:1000 pig C-peptide rabbit Cell 4593 1:500 SignalingGlucagon mouse Abcam ab82270 1:500 Chromogranin A rabbit Abcam ab151601:500 Somatostatin goat Santa Cruz sc-7819  1:1000 Nkx6.1 mouse DSHBF55A12 1:100 MafA rabbit Abcam ab-26405  1:1000 Pdx1 goat R&D AF24191:500 1:300 Glucokinase rabbit Santa Cruz sc-130765 1:200 Ran mouse BD610341  1:1000 Biosciences IHC, immunohistochemistry. FACS, fluorescenceactivated cell sorting. DSHB, Developmental Studies Hybridoma Bank.

TABLE 7 Secondary antibodies used in study. Dilution Dilution for forAntigen Species/Conjugate Manufacturer Catalog # IHC/FACS WesternsGuinea pig IgG goat/AF647 Invitrogen A21450 1:500 Guinea pig IgGdonkey/AF594 Invitrogen A11076 1:500 Guinea pig IgG donkey/DL649 JacksonIR 706-496-148 1:500 Mouse IgG donkey/AF488 Invitrogen A21202 1:500Rabbit IgG donkey/AF488 Invitrogen A21206 1:500 Rabbit IgG goat/AF405Invitrogen A31556 1:500 CD142 mouse/R-PE BD Biosciences 550312 1:10 CD56 mouse/APC BD Biosciences 555518 1:10  CD200 mouse/APC R&D MAB272411:10  CD56 mouse/H V450 BD Biosciences 560361 1:20  Mouse IgG sheep/HRPGE Healthcare NXA931 1:5000 Goat IgG rabbit/HRP Invitrogen 811620 1:5000Rabbit IgG donkey/HRP GE Healthcare NA934 1:5000 AF, Alexa Fluor. DL,DyLight. H, BD Horizon. PE, phycoerythrin. APC, allophycocyanin. HRP,horseradish peroxidase. IR, ImmunoResearch Laboratories.

Glucose-Stimulated Insulin Secretion Assay

In 96-well format, approximately 1000 islet cells amidst 5×105 hESCs(for cell-cell contact and attachment) were plated or, alternatively,approximately 5×105 hESC-derived S6 cells were plated and allowed toattach overnight. Cells were then washed three times in PBS.

Cells were incubated for 1 hour in Kreb's buffer with no glucose (128 mMNaCl, 5 mM KCl, 2.7 mM CaCl2, 1.2 mM MgCl2, 1 mM Na2HPO4, 1.2 mM KH2PO4,5 mM NaHCO3, 10 mM HEPES, 0.1% BSA) at 37° C., 5% CO2, and thenincubated for 60 min in Kreb's buffer with 2.8 mM (low) glucose,followed by 60 min in Kreb's buffer with 16.7 mM (high) glucose, or 30mM KCl in the same conditions. Supernatant fractions after each exposureto glucose were collected and stored at −80° C. until analysis. Insulinconcentrations were measured using the Mouse Ultrasensitive InsulinELISA kit (Alpco, 80-INSMSU-E01), which cross-reacts >100% with humaninsulin. Concentrations were calculated from cubic spline interpolationof a standard curve and normalized to input cell number.

Quantitative RT-PCR

Complementary DNA (cDNA) was made from 4 ng unamplified total RNA withrandom hexamer priming using the High Capacity cDNA ReverseTranscription with RNase Inhibitor kit (Applied Biosystems). One-fourthof the volume of cDNA was used for each TaqMan quantitative reversetranscription polymerase chain reaction (qRT-PCR). Reactions containedtranscript-specific TaqMan probes (Applied Biosystems, Table 8) and FastUniversal PCR Master Mix with no AmpErase UNG (Applied Biosystems).Reactions were run on an Applied Biosystems 7900HT Fast Real-Time PCRSystem with default settings.

Detection thresholds were automatically computed by SDS 2.3 software(Applied Biosystems). Threshold data were analyzed in DataAssist 3.0(Applied Biosystems) using the Comparative Ct (ΔΔCt) relativequantitation method, using β-actin as the endogenous

control.

TABLE 8 TaqMan gene expression assays. Gene (SYMBOL) Probe name β-Actin(ACTB) Hs99999903_m1 Insulin (INS) Hs00355773_m1 Glucagon (GCG)Hs00174967_m1 Somatostatin (SST) Hs00356144_m1

Global Gene Expression Analysis—Microarray

Using the Illumina TotalPrep RNA Amplification kit (Ambion),double-stranded

cDNA was generated following reverse transcription from 100 ng of totalRNA. In vitro transcription overnight with biotin-labeled nucleotidescreated amplified mRNA (cRNA), which was concentrated by vacuumcentrifugation at 30° C. 750 ng cRNA per sample was then hybridized toHuman HT-12 Expression BeadChips (Illumina) using the Whole-GenomeExpression Direct Hybridization kit (Illumina). Finally, chips werescanned on the Illumina Beadstation 500. The chip annotation manifestwas version 4, revision 1. For differential expression analysis and thegeneration of gene lists for functional annotation and pathway analysis,microarray data were processed in GenomeStudio (Illumina, V2011.1). Rawdata were adjusted by background subtraction and rank-invariantnormalization. Before calculating fold change, an offset of 20 was addedto all probe set means to eliminate negative signals. The p-values fordifferences between mean signals were calculated in GenomeStudio byt-test and corrected for multiple hypotheses testing by theBenjamini-Hochberg method in combination with the Illumina custom falsediscovery rate (FDR) model.

Global Gene Expression Analysis—RNA-Seq

Isolated RNA was obtained from 2 biological replicates of HUES8-derivedINS⁺ cells and human adult β cell, as well as one replicate of live andprocessed stage 6 cells. Samples were poly-A purified and converted tocDNA libraries using the Illumina TruSeq protocol, and prepared intoIllumina libraries using the Beckman Coulter Genomics SPRI-works systemusing custom adapters. Ent 3′ barcodes were added during PCR enrichmentand the resulting fragments were evaluated using Agilent BioAnalyzer2100. Samples were multiplexed 2-per-lane for sequencing using theIllumina HiSeq 2000 platform with paired-end read lengths of 80 nt,resulting in 68M to 112M paired reads per sample, and an averagebiological fragment length of 168-179 nt. Reads were aligned to thehuman genome (GRCh37/hg19) using TopHat (version 2.0.4) (Trapnell et al.Nature Protocols. 2012; 7:562-578; Trapnell et al. Nature Biotechnology.2010; 28:511-515) guided by Ensembl gene annotations. RNA-seq enrichmentin annotated Ensemble transcripts was determined by Cuffdiff (version2.0.2) (Trapnell et al. Nature Protocols. 2012; 7:562-578; Trapnell etal. Nature Biotechnology. 2010; 28:511-515) which performed a maximumlikelihood estimate of transcript abundance measured in fragments perkilobase of exon per million fragments mapped (FPKM). Statisticallysignificant transcript differential expression was calculated byCuffdiff using the default negative binomial model, along withassociated p-values.

RNA-Seq Transcript Integrity Analysis

To identify any RNA fragment length bias introduced by the protocol,TopHat aligned RNA-seq read counts from before and after were analyzedat Ensembl annotated exon locations (GRCh37/hg19 version 68) (Flicek etal. Nucleic acids research. 2012; 40:90). Per-bp RNA-seq read coveragewas normalized by total mean log counts and summed over all exonicregions. Transcripts were binned by exonic length and averageper-transcript coverage was adjusted for length (FIG. 10). Intranscripts longer than 2.5 knt (% of genome annotations), the processedsample 3′ bias was greater than the live sample by roughly 2% (AUCdifferential).

Data Preprocessing

For clustering analysis, principal component analysis, gene setenrichment analysis, and all heatmap visualization, the microarray datawere examined using GenePattern (Broad Institute; version 3.3.3). Rawdata were first converted into .gct expression files. Background signal,calculated as the mean of the negative control signal values, wassubtracted from all gene probe values. Expression data were thennormalized by the quantile method. The data were filtered by firstremoving rows (probes) in which all columns (samples) had averagesignals less than 20 and then equating all negative signals to 0.1. Fordifferential expression analysis and the generation of gene lists forfunctional annotation and pathway analysis, microarray data wereprocessed in GenomeStudio (Illumina, V2011.1). As above, raw data wereadjusted by background subtraction and quantile normalization. Beforecalculating fold change, an offset of 20 was added to all probe setmeans to eliminate negative signals. The p values for differencesbetween mean signals were calculated in GenomeStudio by t-test andcorrected for multiple hypotheses testing by the Benjamini-Hochbergmethod incombination with the Illumina custom false discovery rate (FDR)model.

Microarray Expression Clustering

Gene level microarray expression values were generated by GenomeStudio,using rank invariant normalization with background subtraction, andanalyzed using the R package (Suzuki and Shimodaira. Bioinformatics.2006; 22:1540-1542). Per-sample and per-condition (averaging genelevels) hierarchical clustering was performed based on Pearsoncorrelation and dendogram visualizations were drawn. pvclust'smultiscale bootstrap resampling was used (with 500 k iterations) toestimate “approximately unbiased” (AU) p-values indicating thesignificance of each subcluster choice in the hierarchy given theunderlying data.

DAVID Gene Ontology

The representation of gene ontology (GO) biological process terms withinthe lists of differentially expressed genes was assessed using theDatabase for Annotation, Visualization, and Integrated Discovery (DAVID;http://david.abcc.ncifcrf.gov) Bioinformatics Resource. The p-valueswere corrected for multiple hypotheses testing by the Benjamini-HochbergFDR procedure and expressed as a q-value. Terms were ranked by q-value.

Hierarchical Clustering and Principal Component Analysis

In GenePattern, we performed unsupervised hierarchical clustering, acommon approach to group samples by similar expression profiles and tofind the innate sample structure within the data (Eisen et al., 1998).The data were centered by mean subtraction and normalized within eachrow. To place gene expression induction and repression on the samelinear scale, log 2 transformation was performed. Hierarchicalclustering was performed using Pearson's correlation coefficient andpairwise centroid-linkage as the similarity measure and clusteringalgorithm, respectively. Results were visualized in dendrograms, withdistances representing differences in centroid correlation.

To validate groups discovered by hierarchical clustering and verify themain variables driving variation in the data, in GenePattern, weperformed principal components analysis (PCA), a mathematicaltransformation procedure that reduces the high-dimensional, noisy geneexpression data to low-dimensional components that represent major,invariant expression patterns (Raychaudhuri et al., 2000). Preprocesseddata, but not log-transformed, centered, nor row-normalized, were usedto cluster samples according to PCA.

Differential Expression Analysis

Differential expression compared to a reference sample group wasperformed in GenomeStudio to generate t-test-based adjusted p-values fordifferences in expression. Selection of differentially expressed geneswas based on bio-weight analysis (Rosenfeld et al., 2004). Bio-weight isthe product of the log 2 fold change in means and the negative log 10 ofpvalue, thereby providing a smooth transition in data sets between thesetwo parameters. Bioweight accounts for significance defined both bysmall t-test p-values as well as large fold changes. Especially forsmaller sample sets, bio-weight tends to produce a higher truepositivediscovery rate compared to traditionally used fold change-based orp-value based analysis alone (Rosenfeld et al., 2004). Thus, with onemetric, users can identify differentially expressed genes that may be ofboth biological and statistical significance.

Here, we used an absolute value bio-weight cutoff of 2 to determinedifferentially expressed probe sets. This metric is equivalent to atwo-fold change at p=0.01 and a 2.9-fold change at p=0.05.Differentially expressed probes lacking an ENTREZ gene ID were removedfrom further analysis (n=8).

To display heatmaps of differentially expressed genes, unique probeidentifiers from the preceding analyses were exported to GenePattern togenerate a .gct file containing only that subset of probes. Rows werereordered by hierarchical clustering on Pearson correlation or K-meansclustering on Euclidean distance and then visualized with row-normalizedcoloring.

Functional Annotation and Pathway Analysis

To assess the biological patterns of differential gene expression, wemeasured the representation of gene ontology (GO) terms (association ofgene products with their related biological processes and molecularfunctions) within the lists of differentially expressed genes using theDatabase for Annotation, Visualization, and Integrated Discovery (DAVID;http://david.abcc.ncifcrf.gov) Bioinformatics Resource. This allowed usto examine whether any GO term was over- or under-represented ascompared with what is expected occur by chance by a Fisher's exact testwith the EASE (Expression Analysis Systematic Explorer) modification.The p-values were corrected for multiple hypotheses testing by theBenjamini-Hochberg FDR procedure and expressed as a q-value.

Overlap statistics were calculated between the differentially expressedgene list and the category GOTERM_BP_FAT, an agglomeration of all GObiological process terms in DAVID that has removed the broadest, mostoverlapping categories. Terms were ranked by q-value. To further definenon-overlapping categories, we used the DAVID functional annotationclustering tool, which groups terms that share a significant subset ofthe same genes (e.g. “cell cycle” and “cell cycle regulation”). Forannotation clustering, only terms with a nominal EASE score (p-value)less than 0.05 were included, and were grouped under the “lowclassification stringency” setting. The most enriched term (lowestp-value) from each cluster, which usually but not always was the termcontaining the most genes represented, were displayed in pie charts withsection size determined by the number of genes.

Overrepresentation of biological pathways (specifically, signalingnetworks and targets of transcription factors) in the list ofdifferentially expressed genes were visualized in Ingenuity PathwayAnalysis (IPA), which makes use of a proprietary, knowledge-baseddatabase of gene sets. As before, differential expression was defined bybio-weight and pvalues are derived from the probability of observing theoverlap between the differential gene list and the pathway gene list bychance alone.

Generation of Lists of Transcription Factors and Surface Markers

From the lists of differentially expressed genes generated bymicroarray, gene products were filtered by GO terms within GenomeStudio.To determine a list of transcription factors, genes were selected basedon GO terms matching any of the following identifiers (GOIDs) anddefinitions: 3700 (“sequence-specific DNA binding transcription factoractivity”), 30528 (“transcription regulator activity”), 43565(“sequence-specific DNA binding”), or the combination of 6355(“regulation of transcription, DNA-dependent”) and 3677 (“DNA binding”).

To determine a list of candidate surface markers in silico,differentially expressed genes were filtered based on the GO cellularcomponent terms 5887 (“integral to plasma membrane”), or the combinationof 16021 (“integral to membrane”) and 5886 (“plasma membrane”). Fromthis list, transmembrane topology was evaluated using Phobius(http://phobius.sbc.su.se), a hidden Markov model-based predictionprogram (Käll et al., 2004). Proteins with fewer than 6 consecutiveextracellular amino acids or no transmembrane domains were excluded.

Gene Set Enrichment Analysis

Gene set enrichment analysis (GSEA) was used in GenePattern to assessenrichment of defined pathways between sample groups using a rank-basedmetric across the whole dataset rather than using bio-weight cutoffs todefine a subset of differentially expressed genes (Subramanian et al.,2005). This computational method is more sensitive to small concordantchanges that occur broadly across a defined pathway. GSEA was performedwith most default settings, including mean centering, weighted scoring,and using only the maximum expression value of the multiple probesmapping to the same gene. The metric for ranking was signal-to-noiseratio, defined as the difference in means divided by the sum of standarddeviations. Gene sets were randomly permuted for 1000 iterations todetermine the p-value of discovering enriched sets by chance. The geneset database used was canonical pathways from Reactome(http://www.reactome.org) or custom-made β-cell signature gene sets.Publically available gene sets with fewer than 15 members or more than500 members represented in the data set were excluded because enrichmentscores can be hard to interpret beyond in these ranges. A stringent FDRcutoff of q≤0.05 was used to determine statistical significance.

Statistical Weighted Voting

All 1403 features of the β/non-β signature gene sets were used togenerate a class predictor model (Golub et al., 1999). Each feature(probe) was assigned a signal-to-noise statistic that reflects how wella probe correlates with class distinction, defined as S=(μ0−μ1)/(ρ0+ρ!),where 0 and 1 are the classes β-cell and non-β islet cell), μ is theclass mean signal, and ρ is the class standard deviation. Half-waydecision boundaries were defined as Bx=(μ0+μ1)/2 for each probe x. Topredict the class of a sample, each probe casted a vote of win or losebased on the deviation from the decision boundary and weighted by thesignal-to-noise ratio:

Vx=Sx(Gx−Bx).

A vote went to class 0 if sign(VxSx)=1 and to class 1 if sign(VxSx)=−1.The prediction confidence index, reflecting margin of victory, wasdefined as (Vwin−Vlose)/(Vwin+Vlose), where Vwin and Vlose are the sumof votes for or against a class, respectively.

Results Establishment of a Beta-Cell Molecular Signature

Having established the general robustness of gene expression dataobtained from cells purified by modified IC-FACS, we proceeded toinvestigate the transcriptional signature of β-cells. We identified 1403probe sets (3.0% of probes on the array) differentially expressedbetween biological triplicates of β-cells and non-β islet cells (i.e.islets depleted of β-cells) by a t-test-based metric (|bio-weight|>2,where bio-weight=−log 10 p-value×log 2 fold-change). These included 514probes (455 genes; FIG. 12) with expression specific to β-cells, and 889probes (760 genes; FIG. 13) with expression specific to non-β isletcells.

We examined the gene ontology (GO) biological process annotations foreach gene and assessed whether certain terms appeared more often thanwould be expected by chance (FIG. 2A). From the genes enriched in non-βislet cells, the most significantly overrepresented annotations includedones related to adhesion, extracellular matrix, wound response, andvascular development (Benjamini-Hochberg FDR-corrected q<10-6). Theseterms are consistent with the presence of connective tissue within theislet cell mixture, including mesenchyme, endothelial cells, and bloodcells. From the genes enriched in β-cells, significantly overrepresentedannotations included ones related to neuronal differentiation,morphogenesis, and secretion, indicating a concordance between neuronalregulatory pathways and pancreatic endocrine function. Othersignificantly overrepresented terms included those related to regulationof hormone secretion and endocrine pancreas development (q<0.05).Together, these observations demonstrate that the lists ofdifferentially expressed genes in β-cells relative to other cellspresent in the pancreas are generally consistent with expectedbiological functions.

To further confirm the proper sorting of different cell types, weexamined the expression of specific, established markers of variouspancreatic cell types within the list of differentially expressed genes.The non-β islet samples showed significantly higher expression of acinarenzymes (e.g. carboxypeptidase, carbonic anhydrase, trypsins,chymotrypsinogens, elastase, pancreatic lipases), ductal markers(keratin 19, mucin 1, HNF1β), mesenchymal proteins (vimentin),endothelial markers (VCAM1), and the α-cellassociated transcriptionalregulator IRX2 (FIG. 2B). The α-cell transcription factor ARX did notshow a significant difference on our array, though we have not confirmedthis finding by qRT-PCR. Failure of this marker to reach statisticalsignificance may be attributed in part to the relatively small number ofα-cells in the non-β sorted fraction (<30%). In contrast, many knownβ-cell-specific markers were expressed significantly higher in thepurified β-cell population. These included many transcription factors(see below), as well as insulin biosynthesis machinery (e.g. PCSK1,which cleaves proinsulin) and signaling receptors (e.g. ABCC8, thesulfonyl urea receptor and potassium channel that is the target of somediabetes drugs; and GCGR, the glucagon receptor). At the protein level,we confirmed the β-cell-specific expression of PDX1 and thenon-differential expression of glucokinase (GCK), a critical moleculefor glucose sensing in β-cells but also ubiquitously expressed as partof the glycolysis pathway (FIG. 3). These data demonstrate the validityof our experimental approach through their concurrence with previousknowledge of the different pancreatic lineages. Many differentiallyexpressed genes, however, were identified that had no known rolesspecifically in cell types of the pancreas. We have therefore defined acomprehensive molecular signature that distinguishes human β-cells fromother pancreatic cells.

Because cell identity is largely determined by factors that control theexpression of a large number of genes involved in cellular functions, weinvestigated differentially expressed regulators of transcription.Within the β-cell-specific signature gene list, 32 genes weretranscriptional regulators that interact selectively with DNA (Table 9).This list includes well-established β-cell transcription factors likePDX1, MAFA, NKX6-1 (FIG. 2C); known pancreatic development regulatorsnot well-characterized in human cells like NKX2-2 and MNX1; factors withonly some evidence of relevance to β-cell biology, like CLOCK, DACH1,MYT1L, and MLXIPL; and many regulators not previously described at allin pancreatic islets. Thus, we have identified transcriptionalregulators that selectively express in human β-cells.

TABLE 9 Transcription factors specific to human β-cells.ASCL2{circumflex over ( )} CHD7*** CLOCK** DACH1*** DACH2*** DDIT3*ETV5{circumflex over ( )} HOPX{circumflex over ( )} INSM1** MAFA*MLXIPL** MNX1/HLXB9* MYT1L*** NDN*** NKX2-2* NKX6-1* NR0B1{circumflexover ( )} NR3C1** OLIG1{circumflex over ( )} PDX1* PEG3*** PKNOX1**PLAGL1** RXRG*** SIX4*** TOX{circumflex over ( )} TSHZ3{circumflex over( )} TSNAX{circumflex over ( )} ZNF10{circumflex over ( )}ZNF395{circumflex over ( )} ZNF540{circumflex over ( )}ZNF672{circumflex over ( )} Scheme is based on number of publicationslisted in the Type 1 Diabetes database associated with a given gene, asa index for whether the gene has known roles in β-cell biology: *n ≥ 10;**1 < n < 10; ***n = 1; {circumflex over ( )}n = 0.

A secondary goal of this study was to identify β-cell surface markers.Though these molecules are unlikely to determine cell identity in anyactive sense, surface markers are necessary for functional anddevelopmental assays that require isolation of live β-cells.

Analysis of GO cellular component annotations and topology predictionidentified integral plasma membrane proteins with extracellular domainswithin the β-cell signature gene list (Table 10). Though validation ofthese markers was beyond the scope of this thesis, this in silico studyidentified several expected molecules, including ABCC8 and GCGR.

Notably, FXYD2, a regulating subunit of the Na+-K+-ATPase, was recentlyidentified as a β-cell-selective biomarker, though flow cytometricanalyses have not yet been reported (Flamez et al., 2010). Thus, thislist provides a starting point for identifying novel β-cellspecificsurface markers with sorting potential.

TABLE 10 Potential surface markers of human β-cells. ABCA3 CD79B FXYD2KCNB2 NLGN1 PTPRU SLC6A9 ABCC8 CD8A GCGR KCNF1 NPR2 ROBO1 SORL1 ABCG1CDH2 GPR120 KCNG3 NRCAM RTN4 SVOP ACSL1 CDH22 GPR19 KCNH2 PCDHA1 SEMA5ATGFBR3 ATP1B2 CHRNA5 GRIA2 KCNMA1 PCDHA3 SERP2 TRPM2 CACNA1H CYB561KCNH1 KCNQ2 PIGU SLC17A6 TRPM5 CADM1 EFNB3 IGSF11 MADD PLXNA2 SLC43A2TSPAN13 CASR FFAR1 IL17RB NEO1 PRRG2 SLC6A6 UNC5ATranscriptional Profiling of hESC-Derived Insulin+ Cells

We next performed transcriptional profiling to characterize hESC-derivedinsulin+ cells. Global analysis of S6 insulin+ cells compared tounsorted S6 cells revealed that 1222 probes (2.6%) had significantlyincreased signal in insulin+ cells and 1104 (2.3%) had significantlydecreased signal. Clustering analysis of GO biological process termsrevealed that insulin+ cells had higher expression in genes associatedwith ion transport, response to organic substances, cell secretion andregulation of insulin secretion, vesicle-mediated transport, and glucosemetabolism, among other terms (FIG. 4A). These relations suggest thatinsulin+ S6 cells have more potential for endocrine functionality thanthe bulk S6 population. In contrast, unsorted S6 cells were enriched forgenes involved in cell cycle regulation, adhesion, DNA replication,morphogenesis, embryonic development, skeletal development, and vasculardevelopment (FIG. 4B). These associations are suggestive ofproliferating progenitor cells in the process of differentiation intodiverse lineages.

Global analysis of hESC-derived S6 insulin+ cells compared to β-cellsidentified 2326 probes (4.9%) with significantly increased expression inS6 insulin+ cells and 1869 (4.0%) with significantly decreasedexpression. Compared to S6 insulin+ cells, β-cells had higher expressionin genes that participate in lipid and fatty acid metabolism, aminosugar metabolism, cellular secretion, and protein maturation by peptidebond cleavage (FIG. 4C). These processes are consistent with a matureendocrine phenotype that responds to nutrient levels and secretesinsulin. In contrast, compared to β-cells, S6 insulin+ cells had higherexpression of genes that participate in the cell cycle, adhesion, cellmotion, embryonic development, and negative regulation of cellularbiosynethic processes (FIG. 4D).

These processes are suggestive of a relatively immature phenotype inwhich cells are not terminally differentiated and are devoting moreresources to expansion than to biosynthesis.

In both β-cells and S6 insulin+ cells, “response to organic substance”appeared as an enriched term, suggesting that this process isdysregulated in S6 insulin+ cells but GO term analysis is unable todissect apart components of this process and assign directionality.

Candidate Endocrine Gene Analysis

To scrutinize more specific components of endocrine specification, weexamined expression patterns of 73 genes thought to be involved inendocrine pancreas development or function (FIG. 5A). We derived thisapproach from a previous report characterizing hESC-derived cells(Basford et al., 2011) and refined the list of genes based on theliterature on rodent and human islet developmental biology. First, wecompared unsorted S6 cells and S6 insulin+ cells to assess the degree oftheir commitment to the endocrine lineage. Consistent with our findingsthat insulin+ cells express higher insulin, glucagon, and somatostatinthan the bulk S6 population (not shown), we found here that insulin+cells express significantly higher levels of endocrine markers of thepancreas, stomach, and intestine, including CHGB (chromogranin B), GAST(gastrin), GHRL (ghrelin), PPY (pancreatic polypeptide Y), PYY (peptideYY), and IAPP (islet amyloid polypeptide). Of all the genes examined, 40were differentially expressed between unsorted and insulin+ fractions,with all but three of those having higher expression levels in theinsulin+ fraction (FIG. 5B).

Within that list, many transcription factors that control endocrine cellidentity were more highly expressed in the S6 insulin+ than the unsortedfraction. In contrast, the transcriptional regulators HES1, NOTCH1, andSOX9, which are involved in earlier patterning of gut endoderm, showedhigher expression in the unsorted S6 fraction. Insulin+ cells expressedmost genes involved in endocrine function. These included manycomponents involved in exocytosis (RIMS2, SNAP25, STX1A, SYP, SYT7, andSTXBP1) and KATP and Ca2+ ion channels critical for islet secretoryfunction (including genes that encode Kir6.2, SUR1, CaV2.1, CaV1.2).Additionally, GCK, which functions as a glucose sensor and metabolicregulator, was expressed more highly in insulin+ cells. FFAR1, a fattyacid receptor that modulates β-cell metabolism, and SLC30A8, a zinctransporter implicated in insulin granule maturation, were alsoelevated. Taken together, these expression patterns strongly suggestthat compared to the bulk S6 population, the insulin+ fraction moreclosely resemble endocrine lineage cells, albeit heterogeneous orpolyhormonal.

Next, we compared S6 insulin+ cells to sorted β-cells to evaluate thecorrespondence between hESC-derived cells and mature ones. Of the genesexamined, 30 were differentially expressed (FIG. 5C). Compared to S6insulin+ cells, β-cells expressed low levels of GAST, GHRL, and PYY, buthigh levels of IAPP and CHGB, consistent with the phenotype of matureβ-cells. The early endoderm transcription factors HES1 and SOX9 wereequally expressed in β-cells and S6 insulin+ cells, but NOTCH1 wasupregulated in S6 insulin+ cells. A cluster of transcription factorsthat participate in early endocrine lineage specification were expressedat similar levels (NEUROG3, NEUROD1, MAFB, and PAX6), though others(ISL1, PROX1, and FOXA3) were found at higher levels in S6 insulin+cells.

Of the genes involved in both early pancreas development and matureislet function, PDX1 levels were similar, but several were upregulatedin S6 insulin+ cells (FOXA1, HNF1β, SOX4, and PBX1). Notably, β-cellshad higher levels of the known β-cell-specific factors MAFA, NKX6-1, andMNX1, whereas S6 insulin+ expressed significantly more of theα-cellspecific factors ARX and IRX2, raising the hypothesis that S6insulin+ cells express a transcriptional program gravitating towardsα-cell fate. In total, 15 of 36 transcription factors examined weredifferentially expressed (both up and downregulation) in S6 insulin+cells compared to mature β-cells, indicating that large differences intheir identities exist.

These differences were also reflected in genes controlling β-cellfunction. S6 insulin+ cells expressed significantly less of thesignaling factors GCGR and the estrogen receptor (ESR1). These cellsalso exhibited lower levels of a cluster of proteins involved in insulinbiosynthesis, processing, and granule exocytosis (PCSK1 and 2, SLC30A8,STXBP1, and VAMP2). However, S6 insulin+ cells had similar levels of GCKand SLC2A1, the primary glucose transporter in β-cells, and lower levelsof G6PC2, which is proposed to counteract GCK. Interestingly, S6insulin+ cells expressed similar or higher levels of all the Ca2+ and K+ion channels examined than β-cells did. These data suggest that, atleast on the mRNA level, a deficiency of transporters and glycolyticgenes cannot explain the lack of stimulus-secretion coupling in S6insulin+ cells, while a deficiency in insulin processing might. On thewhole, this approach of examining a list of candidate genes has revealedthe dysregulation of a large number of transcription factors andfunctional elements thought to be important in β-cells.

Human β Cell Maturation

Study of human fetal development has been hampered by the absence ofreporters and cell surface markers to permit sorting of specific celltypes derived ex vivo, as well as the scarcity of human fetal materialfor study. Researchers have thus relied on studies in model organisms,primarily the mouse, as the basis for understanding human developmentand optimizing directed differentiation. Recently, our laboratoryidentified differential gene expression patterns that distinguish fetalβ cells from adult β cells in the mouse (Blum et al. Naturebiotechnology. 2012; 30:261-264). To uncover markers of human β cellmaturation, we performed a purification and transcriptome-wide molecularcharacterization of human fetal and adult β cells.

Human pancreata at 15-16 weeks gestational age were used, since β cellsat this stage are immature and glucose non-responsive (Hayek andBeattie. J. Clinical Endocrinology and Metabolism. 1997; 82:2471-2476;Beattie et al. Cell Transplantation. 1994; 3:421-426). Adult humancadaveric islets and fetal pancreata were dispersed, stained for insulinand FACS sorted. RNA was isolated and analyzed by Illumina microarrays(FIG. 6A).

Human β cells maturation between gestational week 16 and adulthood ischaracterized by gene expression changes in 643 genes of which 39 weretranscription factors (p<0.05, fold change >3) (FIG. 6B). UCN3, which weidentified previously as a marker of mouse β cell maturation wasexpressed 1.1× fold higher in sorted human adult β cells over fetal βcells, indicating that UCN3 expression does not significantly changebetween human week 16 and adult β cells (FIG. 6C). Collectively, thedifferentially expressed genes presented in this study could be used asgenetic markers of human β cell maturation. Gene Ontology analysis ofall differentially expressed genes (p<0.05) suggests that severalmetabolic and secretory biological processes are significantly enrichedin adult β cells over fetal β cells (FIG. 6D).

Together, this data provides the first transcriptome-wide molecularcharacterization of human fetal and adult β cells. This analysis ofgenes differentially expressed between fetal and adult β cells points tosignificant differences between mouse and human β cell maturation.Further analysis of β cells at multiple time-points during human andmouse development is necessary to elucidate these species divergence.

Transcriptional Differences Between hES-Derived INS⁺ Cells and HumanAdult β Cells

The goal of hPSC directed differentiation is to generate functionalhuman β cells. We therefore compared gene expression by microarray andRNA-seq between hPSC-INS⁺ cells and adult human β cells. We firstfocused our analysis on 152 endocrine lineage genes. Expression of 26 ofthe 152 genes was significantly different between adult β cells andhPSC-INS⁺ cells based on microarray analysis (>3 fold, p<0.05). RNA-seqanalysis of two samples of human adult INS⁺ cells and two samples ofHUES8-INS⁺ cells confirmed 24/26 genes as differentially expressed >3fold (FIG. 7A). Using immunofluorescent staining, we confirmed the lackof expression of NKX6-1 and relatively heterogeneous expression of PDX1and MAFA in hPSC-INS⁺ cells (FIG. 7B). PDX1, MAFA and NKX6-1 arerobustly expressed in normal human β cells and in vivo maturedhPSC-derived INS⁺ cells (Rezania et al. Diabetes. 2012; 61(8):2016-29).

Many of the incorrectly expressed transcription factors have known rolesin endocrine subtype specification: PDX1, NKX6-1, MNX1, FOXA1, ARX, PAX4and IRX2. Several misexpressed genes from the list are involved inglucose stimulated insulin secretion (GSIS) MAFA, PAX4, GHRL, CHRB,PROX1, KCNK1, KCNK3. Expression of genes sets involved in sterolmetabolism/biosynthesis indicates the presence of liver-enriched geneticprograms in hPSC-INS⁺ cells.

Since human fetal β cells are also immature and non-functional withrespect to accurate GSIS, we wondered which of the genes were alsomisexpressed in human fetal β cells. Interestingly, the endocrinesubtype specification genes were not misexpressed in human fetal β cellswhile the GSIS genes were (FIG. 7A). This suggests two possibly distinctchallenges to produce functional human β cells from hPSC-INS⁺ cells: 1)β cell lineage commitment and 2) functional maturation. Our observationssupport the hypothesis that hPSC-INS⁺ cells resemble human fetal cellsthat are not (yet) committed to the β cell lineage. The modulation ofthese genes along with others with the same pattern of expression may becritical for the acquisition of mature glucose response.

We next expanded the analysis to the whole genome. Of the 755 genes thatwere differentially expressed (p<0.05, >3 fold) between hPSC-INS⁺ cellsand human β cells, 583 were confirmed by RNA-Seq (>3 fold). We present alist of all differentially expressed transcription factors as they areof particular interest for they role in modulating cell fates (FIG. 7C).Genes identified here can be used as markers for differentiation intohuman β cells or may be manipulated to direct the conversion ofhPSC-INS⁺ cells into human functional β cells. Additionally, geneontology analysis of all differentially expressed genes (p<0.05 bymicroarray) identified 22 statistically enriched (q<0.05) biologicalprocesses in hPSC-INS⁺ cells (Table 11 below). Among the ten mostdifferentially expressed processes (FIG. 7D) three involvecholesterol/sterol biosynthesis or metabolism indicating that hPSC-INS⁺cells additionally express non-pancreatic, liver-specific geneticpathways.

TABLE 11 GO Biological Pathways enriched in hPSC-INS+ cells GeneOntology Biological Process Benjamini q value Enriched cytoskeletonorganization 0.0014108 in hPSC-INS⁺ sterol biosynthetic process0.0014891 cells cholesterol biosynthetic process 0.0018188 cellmorphogenesis 0.0018485 cellular component morphogenesis 0.0045675 actinfilament-based process 0.0150359 actin cytoskeleton organization0.0167663 sterol metabolic process 0.0174035 cell projectionorganization 0.0179661 neuron projection development 0.0185401cholesterol metabolic process 0.0187551 neuron development 0.0199759cell part morphogenesis 0.0201410 neuron projection morphogenesis0.0213534 cell projection morphogenesis 0.0228888 lipid transport0.0264480 lipid localization 0.0286305 isoprenoid biosynthetic process0.0295110 neuron differentiation 0.0301086 lipoprotein particleclearance 0.0440558 response to organic substance 0.0444088 steroidbiosynthetic process 0.0456816

Gene Set and Pathway Analysis

We wished to take a less subjectively biased and more systems-basedapproach in identifying dysregulated elements, so we next performed geneset enrichment analysis (GSEA) using canonical pathways from Reactome.This method allows the comparison of sample groups across a large numberof manually curated gene lists that have known biological relationships,in a way that is more sensitive than traditional differential expressionanalysis to small, but concordant, changes that occur broadly across adefined pathway (Subramanian et al., 2005). GSEA identified only threeReactome gene sets that were significantly enriched in β-cells comparedto S6 insulin+ cells after adjusting for multiple hypotheses testing(FDR q<0.05; FIG. 8A). One was “insulin synthesis and secretion”(q=0.031), confirming our previous findings that on the transcriptionallevel, S6 insulin+ cells have defective insulin processing machinery.Genes in the leading edge (most enriched) included ones tested in ourcandidate approach (e.g. PCSK1 and 2, VAMP2, STXBP1, etc.) and othersless specific, but nevertheless important, for β-cell function (e.g.signal peptidases, protein localization signal receptors, and ribosomalproteins). A second enriched pathway was “metal ion SLC transporters”(q=0.027). Leading edge analysis revealed that SLC30A8 was the mostenriched member in β-cells, confirming our previous candidate-basedfindings, within a list of 11 transporters, most of them zinc carriers.Zinc is important in insulin granule maturation (Chimienti et al., 2004;Lemaire et al., 2009), so this result suggests that an inability toproduce zinc flux may contribute to the dysfunction of S6 insulin+cells.

Interestingly, the most enriched pathway in β-cells compared to S6insulin+ cells was the “unfolded protein response” (UPR; q<0.001). Weconfirmed this association using Ingenuity Pathway Analysis (IPA), whichrelies on a different algorithm and proprietary, but similar gene lists(FIG. 8B). Members of this pathway, including PERK (EIF2AK3) and IRE1α,have been implicated in mature β-cell function through animal and humangenetics studies. In particular, dysregulation of the UPR pathway candisturb proinsulin synthesis, intracellular insulin trafficking, andexpression of β-cell-related genes (see Chapter 4.2 for discussion). Infact, IPA revealed that a transcription factor downstream in the UPRpathway, XBP1, is expressed significantly lower in S6 insulin+ cells andregulates or interacts with many of the other genes downregulated in S6insulin+ cells, including the exocytosis proteins VAMP2 and VAMP4, andthe transcription factors MAFA, ESR1, and DDIT3 (FIG. 8C). The overlapbetween the list of genes with depressed expression in S6 insulin+ cellsand the list of genes directly downstream of XBP1 was the moststatistically significant of any transcription factor-based network inIPA (p=0.00131). These data strongly indicate that the UPR pathway isdysregulated in S6 insulin+ cells and may account for part of thebroader functional defects observed.

Design and interpretation of the preceding candidate gene evaluationsand knowledge-based pathway analyses are necessarily limited and biasedby the available experimental evidence, which are largely derived fromanimal or cell culture models. In the case of transcription factors,genes can have vaguely defined effects on cell identity that vary acrossdevelopmental stages and species. Our evaluation of transcriptionfactors derived from the literature on pancreatic development andfunction revealed many genes that were overexpressed and many that wereunderexpressed in S6 insulin+ cells compared to β-cells.

The implications of these varied differences on mature cell typespecification remained unclear. Hence, we hypothesized that theexamination of human β-cell-specific genes could clarify how closely S6insulin+ cells resemble β-cells as opposed to other pancreatic cells.

Beta-Cell Molecular Signature Expression

Towards this end, we asked whether the β-cell molecular signaturepreviously generated could inform the characterization of hESC-deriveddifferentiation products. We assessed the expression of the 1403 probesin the signature (up and downregulated in β-cells relative to non-βislet cells) in unsorted S6 cells and the insulin+ fraction. First, wedefined the 458 genes preferentially expressed in β-cells as the “β-cellgene set” and the 775 genes preferentially expressed in β-depleted isletcells as the “non-β gene set.” GSEA using these two gene sets and arank-based metric revealed that, in comparison to S6 insulin+ cells,unsorted S6 cells were significantly enriched for non-β genes (p<0.001;FIG. 9A). Conversely, in comparison to unsorted S6 cells, S6 insulin+cells were significantly enriched for β-cell genes (p<0.001). These datasimply indicate that the insulin+ fraction is more β-cell-like while thebulk S6 population is more akin to a mixed population of pancreatictissue exclusive of β-cells.

Hierarchical clustering based on row-normalized signature probes led toa similar conclusion. S6 insulin+ cells clustered more closely withβ-cells while unsorted S6 cells clustered more closely with non-β isletcells (FIG. 9B). Inspection of the heatmap and dendrogram, however,revealed that many differences within each branch existed. In fact, 717of 1403 probes were significantly different between β-cells and S6insulin+ cells (|bioweight|>2; mean signals listed in FIG. 12 and FIG.13). To investigate further the absolute degree of similarity betweenβ-cells and S6 insulin+ cells (as opposed to relative difference basedon comparison to unsorted S6 cells), we used a statistical weightedvoting model using the 1403 probe signature (Golub et al., 1999). Eachprobe votes for classification as either β-cell or non-β cell dependingon whether the expression level in the sample of interest is closer tothe mean of levels in β-cells or non-β cells. Further, the votes areweighted by how well the probe is correlated with the difference betweenβ-cell and non-β cell samples. Our model classified unsorted S6 cells asnon-β pancreatic cells with modest confidence, but S6 insulin+ cellscould not be confidently classified as β-cells (FIG. 9C). These dataindicate that while S6 cells as a whole are marginally reminiscent of amixed population of pancreatic cells, the cells in the insulin+ fractiondo not significantly resemble mature β-cells in particular.

To hone in on the salient differences, we examined the transcriptionfactors belonging to the β-cell/non-β signature set that weredifferentially expressed between S6 insulin+ cells and β-cells(|bio-weight|>2). Of the 20 factors having higher expression levels inβ-cells than S6 insulin+ cells, 18 are normally β-cell-selective in thepancreas (FIG. 10A). Conversely, of the 29 transcription factors havinghigher expression levels in S6 insulin+ cells, all are normallyexpressed more in non-β islet cells than in β-cells (FIG. 10A). Thisremarkable degree of category concordance suggests that S6 insulin+cells are systematically expressing transcription factors that definenon-β cell identity while underexpressing transcription factors thatdefine β-cell identity.

The list of misexpressed transcription factors included known and novelgenes in islet biology. Among the β-cell-specific factors examined viaour candidate approach were NKX6-1, MAFA, and MNX1. NKX6-1 mRNA wasexpressed 14-fold higher in β-cells than S6 insulin+ cells, a differencewe confirmed here by immunohistochemistry: almost no coexpression ofc-peptide (the by-product of de novo insulin synthesis) and Nkx6.1protein was detected in S6 culture (FIG. 10B). The many Nkx6.1+ cellspresent were likely less differentiated pancreatic progenitors, as Pdx1was also observed in a large number of S6 cells (FIG. 10D). MAFA mRNAwas expressed 6.5-fold higher in β-cells than in S6 insulin+ cells; asexpected, upon staining, we observed that only a minority of c-peptide+cells expressed detectable MafA protein. In contrast, PDX1 mRNA levelswere not significantly different between β-cells and S6 insulin+ cellsand accordingly, Pdx1 protein was highly expressed in all c-peptide+cells (FIG. 10D). Among the differentially expressed non-β-specificfactors identified both in our candidate approach and the signature genelist informed approach were IRX2, HNF1β, and SOX4. Taken together, thedata imply that β-cell signature genes may serve as informative,specific markers for monitoring in vitro differentiation. This focusedlist of transcription factors elucidates key differences between S6insulin+ cells and β-cells and provides potential targets for improvingdirected differentiation.

Discussion Beta-Cell Transcriptome

We generated a gene expression atlas specific to β-cells that correlatedwith a subset of findings by Grompe and colleagues, who used a surfacemarker FACS approach that partially purified β-cells with δ-cells(Dorrell et al., 2011). Out of the 43 genes that the prior study listedwith >20-fold elevated expression in putative sorted β-cells relative tosorted α-cells, we found significant enrichment in 15 when comparingβ-cells to mixed non-β islet cells: ASB9, CAPN11, CDH22, CLIC6, CNGA3,DCX, DGKB, DLK1, GLT25D2, HADH, IGSF11, PLCH2, PRPH, SCD5, SGIP1,SLC17A6, and SOD3. Among these are genes with known human β-cellfunctions. HADH encodes an enzyme involved in mitochondrial fatty acidoxidation and regulation of insulin secretion (Hardy et al., 2007),inactivating mutations in which cause congenital hyperinsulinism(Clayton et al., 2001).

Others are suspected human β-cell factors. The locus of DGKB, whichencodes a kinase involved in glycerolipid metabolism, is associated withtype 2 diabetes (Dupuis et al., 2010) and impaired glucose-stimulatedinsulin secretion (Boesgaard et al., 2010). In addition, the imprintedDLK1 region is associated with paternally inherited risk of T1DM(Wallace et al., 2010). Due to the design of our study, we can nowconfidently assign the expression of these genes to the β-cells withinthe adult human pancreatic islet.

A notable finding of this study is that adult human β-cells express onlya small set of unique transcription factors. We identified 31 such genesthat have varying levels of existing evidence for a role in β-cellbiology. Most reassuringly, gene targeting experiments in mice haverevealed critical, now canonical, roles for MAFA (Matsuoka et al., 2004;Zhao et al., 2005), MNX1/HLXB9 (Harrison et al., 1999; Li et al., 1999),NKX2-2 (Sussel et al., 1998), NKX6-1 (Sander et al., 2000), and PDX1(Jonsson et al., 1994) in β-cell specification, maturation, andfunction. Human genetics have verified some of these findings. Mostnotably, various mutations in PDX1 cause maturity onset diabetes of theyoung type IV (MODY4), pancreatic agenesis (Stoffers et al., 1997), andsusceptibility to T2DM (Hani et al., 1999; Macfarlane et al., 1999).Polymorphisms in human MAFA are associated with T1DM susceptibility(Noso et al., 2010). These data corroborate our transcription factorexpression profiles that robustly show for the first time theβ-cell-specificity of these factors in humans.

A handful of other transcription factors identified have plausible rolesin β-cells and merit discussion. First, in the case of CLOCK,conditional ablation of this circadian oscillator resulted in diabetesin mice due to detective stimulus-secretion coupling in β-cells(Marcheva et al., 2010). Two circadian rhythm regulators (MTNR1B, CRY2)have been linked to fasting glucose levels in human genome-wideassociation studies (Dupuis et al., 2010). Though these two genes werenot identified as β-cell-specific in our study, they do provide evidencefor a role of this CLOCK-related pathway in glucose homeostasis. Second,in the case of DACH1, deletion in mice blocked the perinatal burst ofdifferentiated β-cell expansion, resulting in lower β-cell mass in theadult (Kalousova et al., 2010). This gene and its homologues appear toplay a conserved role from zebrafish to mice in regulating theproliferation of pancreatic endocrine cells. Third, the expression ofHOPX in sorted β-cells was previously observed and confirmed on theprotein level (Dorrell et al., 2011). Though its function in thepancreas is unclear, there is evidence that in the developing heart andlung, HOPX functions downstream of NKX2-1 and NKX2-5, respectively (Chenet al., 2002; Yin et al., 2006). Since human β-cells also expressNK-family homeobox genes, HOPX may play a role in endocrine lineagespecification. Fourth, MLXIPL (ChREBP) regulates glycolytic andlipogenic gene expression in the mouse β-cell line MIN6 in aglucose-dependent manner (Wang and Wollheim, 2002; Da Silva Xavier etal., 2006). Inactivation or overexpression of the transcription factorhave also been shown to modulate levels of PDX1, MAFA, GCK, and INS inMIN6 cells (da Silva Xavier et al., 2010). MLXIPL may therefore be animportant regulator of β-cell gene expression that responds to elevatedglucose concentrations. Fifth is MYTL1, which has not been previouslydescribed in normal adult or embryonic pancreas. When its paralog, MYT1,was knocked out in the developing mouse pancreas, the mutant animalsexhibited mildly attenuated glucose-stimulated insulin secretion and,interestingly, abnormal polyhormonal cells within the adult islets (Wanget al., 2007). In these knockouts, MYTL1 was upregulated and, theauthors speculated, reduced the full effects of MYT1 deletion via aredundant, compensatory mechanism. These data point to a potentialability for MYT1L to regulate β-cell function or differentiation.

Finally, PEG3 is an imprinted gene whose product inhibits Wnt signalingin human cells by binding to the signal transduction protein β-cateninand promoting its degradation (Jiang et al., 2010). Exposure to Wnt3a (aWnt family member expressed in human islets) or forced expression ofactivated β-catenin causes the proliferation of differentiated mouseβ-cells in culture and in vivo (Rulifson et al., 2007). In humans,hypomethylation of PEG3 and some other imprinted loci, caused by themutation of an upstream transcription factor, is associated withtransient neonatal diabetes mellitus (Mackay et al., 2008). These datasuggest a role for PEG3 in promoting or maintaining β-cell mass.

Collectively, however, these gene expression observations provideplausible heuristics for finding reprogramming agents that enforceβ-cell identity. We further speculate that a combination of humangenetics studies and our functional genomics approach will providefocused insight on the unique roles of genes in human β-cell biology.

Immature Phenotype of hESC-Derived Insulin+ Cells

Glucose-stimulated insulin secretion in hESC-derived cells remainselusive. We found that S6 insulin+ cells secreted insulin above baselineonly under direct membrane depolarization. On a per cell basis,KCl-induced insulin release occured at lower levels in S6 cells than inislets. Consistent with this functional finding, we detected lowerexpression of many genes involved in insulin processing and granuleexocytosis (e.g. PCSK1 and 2, SLC30A8/ZnT8, VAMP2, and STXBP1). Theidentification of SLC30A8 as a dysregulated element was corroborated bypathway analysis and stands out because ample evidence points to itsimportance in humans. A polymorphism within the human SLC30A8 gene isassociated with indices of β-cell function (Dupuis et al., 2010) andsusceptibility to T2DM, a genome-wide significant finding that has beenwell-replicated (Saxena et al., 2007; Scott et al., 2007; Sladek et al.,2007; Zeggini et al., 2007).

The plainest hypotheses for explaining the lack of glucoseresponsiveness, regardless of total insulin content, are deficiencies inglucose sensing and metabolism, or in ion channels required fortriggering secretion. Unfortunately, we found few remarkable deficits inthe glucose transporter Glut1, glycolytic machinery, and KATP and Ca2+ion channel expression, consistent with a previous report onhESC-derived cells (Basford et al., 2011). That prior report diddemonstrate reduced levels of functional ion channels despite normalmRNA levels, but electrophysiological analysis of the insulin+ cellsfrom our protocol remains a future goal. In a search for more satisfyinghypotheses that would provide targets for the improvement of directeddifferentiation, we then examined transcription factors and members ofsignaling pathways.

The deficiency of the glucagon receptor (GCGR) in hESC-derived insulin+cells is noteworthy. In mice, overexpression of GCGR specifically inβ-cells resulted in enhanced β-cell function and mass (Gelling et al.,2009). In humans, different genetic variants in GCGR are associated withtype 2 diabetes (Hager et al., 1995) and, in the case of one homozygousmissense mutation, hyperglucagonemia due to α-cell hyperplasia (Zhou etal., 2009). In the latter instance, the patient's α-cells also expressedpancreatic polypeptide, which is normally produced by PP cells of thepancreatic islets, suggesting that, in a background of GCGR deficiency,these glucagon-expressing cells have an immature phenotype. Though thelimited pancreas biopsy from this patient did not containglucagon+/insulin+ cells, such polyhormonal cells were readily observedin adult GCGR knockout mice (Vuguin et al., 2006). Additionally, therewere a larger proportion of α-cells and δ-cells in these animals, andthe α-cells expressed the β-cell markers SLC2A2/GLUT2 and PDX1, whilethe β-cells exhibited lower than normal levels of insulin, GLUT2, MAFA,PDX1, and PCSK1. This immature phenotype is strikingly similar to thatof insulin+ cells produced in vitro. In this study, we found thathESC-derived insulin+ cells frequently co-expressed other endocrinehormones, expressed α-cell transcription factors ARX and IRX2, and hadlower levels of MAFA, GLUT2, and PCSK1 compared to mature β-cells. Theseresults suggest that activating glucagon signaling could aid thematuration of hESC-derived insulin+ cells.

This study additionally found markedly decreased levels of XBP1, PERK,eIF2α, and other members of the unfolded protein response (UPR)signaling pathways in hESC-derived insulin+ cells compared to adulthuman β-cells. Normally, pancreatic β-cell survival and function dependon the UPR pathways coordinated by PERK and eIF2α, on one branch, or byIRE1α and XBP1, on the other (FIG. 6B). With respect to the firstbranch, in humans, mutations in the kinase PERK underlieWolcott-Rallison syndrome, which is characterized by permanent neonatalor early infancy insulin-dependent diabetes (Delépine et al., 2000).Evidence from mouse models indicates that PERK is required for fetalβ-cell differentiation and, in the adult organism, PERK regulatesproinsulin trafficking and quality control in response to metabolicdemands (Zhang et al., 2006; Gupta et al., 2010). PERK phosphorylateseIF2α, which attenuates mRNA translation in β-cells. When the eIF2αphosphorylation site was inducibly mutated in mouse β-cells, the animalsexperienced severe diabetes within a few weeks due to unregulatedproinsulin translation, defective protein trafficking, and reducedexpression of the β-cell genes PDX1, MAFA, GLUT2, IAPP, and insulin(Back et al., 2009).

With respect to the second branch, very recent evidence shows that afeedback loop involving IRE1a and its splicing product XBP1 is necessaryfor optimal insulin secretion and glucose homeostasis (Lee et al.,2011). β-cell-specific ablation of the transcription factor XBP1 in micemarkedly reduced the number of insulin granules in β-cells, impaired theprocessing of proinsulin, attenuated glucose-stimulated insulinsecretion, and inhibited β-cell proliferation. In addition to theeffects on protein processing, deficiency of XBP1 caused hyperactivationof its upstream activator, IRE1α, which can degrade a set of mRNAsencoding insulin, PCSK1, and PCSK2 (Lipson et al., 2006, 2008; Lee etal., 2011).

Collectively, these data point to the UPR signaling pathway as anexciting target for enhancing insulin biosynthesis in hESC-derivedcells. Further targets were suggested in our examination ofβ-cell-specific transcription factors in hESC-derived insulin+ cells. Inparticular, MAFA, NKX6-1, and MNX1 were among those underexpressed in S6insulin+ cells compared to mature β-cells. These and others withhypothesized roles in β-cells (see above), such as HOPX, MYT1L, CLOCK,and DACH1, together form a high priority list of factors to promoteβ-cell identity following the immature endocrine cell stages of directeddifferentiation. In addition, factors not preferentially expressed inβ-cells, including ARX, IRX2, and HNF1β, represent potential targets forthe inhibition of polyhormonal fates.

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1. A method comprising: (a) differentiating in vitro a population ofcells comprising stem cells and/or pancreatic progenitor cells to arriveat a population of differentiated cells that express ESR1 and G6PC2genes, wherein the differentiating comprises contacting the populationof cells with at least one of Activin A, a fibroblast growth factor, asonic hedgehog pathway antagonist, a Rho-associated kinase inhibitor, aprotein kinase C agonist, and a TFG-β signaling inhibitor; and (b)measuring expression of ESR1 and G6PC2 genes in the population ofdifferentiated cells, wherein detection of expression indicates thepresence of one or more β-cells capable of glucose-stimulated insulinsecretion (GSIS).
 2. A method comprising: (a) measuring expression ofESR1 and G6PC2 genes in a population of cells to identify at least onecell expressing ESR1 and G6PC2, wherein said measuring is conducted withat least one binding assay; and (b) administering the population ofcells to a subject upon detection of expression of the ESR1 and G6PC2genes. 3-13. (canceled)
 14. The method of claim 1, wherein the stemcells are selected from the group consisting of human embryonic stemcells (hESCs), induced pluripotent stem cells (iPSCs), and combinationsthereof. 15.-19. (canceled)
 20. The method of claim 1, wherein the oneor more β-cells comprises at least one mature β-cell. 21-24. (canceled)25. The method of claim 1, further comprising sorting the one or moreβ-cells to separate immature and mature β-cells.
 26. The method of claim25, wherein sorting the one or more β-cells to separate the immature andmature β-cells comprises conducting fluorescence-activated cell sorting(FACS).
 27. (canceled)
 28. The method of claim 25, further comprisingquantifying the sorted β-cells.
 29. The method of claim 25 furthercomprising preserving the sorted β-cells.
 30. The method of claim 1,further comprising conducting a GSIS assay on the one or more β-cells.31-32. (canceled)
 33. The method of claim 1, wherein the one or moreβ-cells are derived from human cells selected from the group consistingof human embryonic stem cells, reprogrammed human somatic cells, andinduced human pluripotent stem cells. 34-45. (canceled)
 46. The methodof claim 1, wherein the sonic hedgehog pathway antagonist is SANT-1. 47.The method of claim 1, wherein the TGF-β signaling inhibitor is Alk5i.48. The method of claim 1, wherein the fibroblast growth factor iskeratinocyte growth factor (KGF).
 49. The method of claim 1, wherein theRho-associated kinase inhibitor is Y27632.
 50. The method of claim 1,wherein the protein kinase C agonist is PDBU.
 51. The method of claim 1,wherein said measuring is conducted with at least one binding assay. 52.The method of claim 1, further comprising administering the populationof differentiated cells to a subject.
 53. The method of claim 52,further comprising enriching for the one or more β-cells prior to saidadministering.
 54. The method of claim 2, wherein the population ofcells is obtained from an in vitro source.
 55. The method of claim 2,wherein the population of cells is obtained from an in vivo source. 56.The method of claim 2, wherein the at least one cell expressing ESR1 andG6PC2 is a β-cell.
 57. The method of claim 56, further comprisingidentifying the at least one cell expressing ESR1 and G6PC2 as theβ-cell.
 58. The method of claim 56, further comprising enriching theβ-cell prior to said administering the population of cells to a subject.59. The method of claim 56, wherein the β-cell is a mature β-cell. 60.The method of claim 59, further comprising sorting the population ofcells to separate the mature β-cell from one or more immature β-cells.61. The method of claim 56, further comprising conducting a GSIS assayon the β-cell.
 62. The method of claim 2, wherein the population ofcells is derived from human cells selected from the group consisting ofhuman embryonic stem cells, reprogrammed human somatic cells, andinduced human pluripotent stem cells.